Treatment of Diseases by Concurrently Eliciting Remyelination Effects and Immunomodulatory Effects Using Selective RXR Agonists

ABSTRACT

The present specification provides RXR agonists with both remyelination promotion and immunomodulatory activities, compositions comprising such RXR agonists, and methods using such compounds and compositions to treat a demyelination-related disorder by both promoting remyelination of neurons and modulating the immune system.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. Provisional PatentApplication 61/887,529, filed Oct. 7, 2013 and is a continuation-in-partof U.S. patent application Ser. No. 13/714,051 filed Dec. 13, 2012,which claims the benefit of U.S. Provisional Patent Application61/570,182, filed Dec. 13, 2011, all of which are hereby incorporated byreference in their entirety.

GOVERNMENT SUPPORT

This invention was made with government support under R01-CA062275 andR01-AT005382 awarded by National Institutes of Health (NIH). Thegovernment has certain rights in the invention.

FIELD

The present invention is directed to methods of inducing remyelinationin demyelination-associated disorders using RXR agonists.

BACKGROUND

Attempts to treat autoimmune disorders have met with limited success.This is due, in part, to the fact that the etiology of autoimmunedisorders is a complex response based in part on a combination offactors, including, without limitation, genetic make-up of individual,gender or hormonal status, bacterial or viral infection, metal orchemical toxin exposure, vaccinations or immunizations, stress, trauma,smoking and/or nutritional deficiencies. Therefore, compounds,compositions, and methods that can reduce a symptom associated with anautoimmune disorder, inflammation associated with an autoimmunedisorder, and/or a transplant rejection would be highly desirable.

Naïve CD4⁺ T cells play a central role in immune protection. They do sothrough their capacity to help B cells make antibodies, to inducemacrophages to develop enhanced microbicidal activity, to recruitneutrophils, eosinophils, and basophils to sites of infection andinflammation, and, through their production of cytokines and chemokines,to orchestrate the full panoply of immune responses. Naïve CD4⁺ T cellsare multipotential precursors that differentiate into various T cellsubsets, such as, e.g., T helper (Th) cells (also called T effectorcells) and T regulatory (Treg) cells. T helper cells are characterizedby their distinct functions and include Th1, Th2, and Th17. Th1 cellsaid in the clearance of intracellular bacteria and viruses, secreteIFN-γ in response to the cytokine interleukin-12 (IL-12), and requirethe transcription factors T-box21 (T-bet) and signal transducer andactivator of transcription 1 (Stat1) and (Stat4). Th2 cells help controlextracellular pathogens, secrete the cytokines IL-4, IL-5 and IL-13, andrequire transcription factors GATA-binding protein 3 (GATA-3) and Stat6.Th17 cells provide protection against fungi and various otherextracellular bacteria, secrete the pro-inflammatory cytokine IL-17A,and express the transcription factor retinoic acid orphan receptor gamma(RORγt). Treg cells play a critical role in maintaining self-toleranceas well as in regulating immune responses and express the transcriptionfactor forkhead box P3 (FoxP3). Tregs normally develop in the thymus,but can also differentiate from naïve CD4⁺ cells stimulated with TGF-βand IL-2. Development and differentiation of Treg cells, as well asexpression of FoxP3, require the transcription factor Stat5.

Although several cytokines participate in Th17 cell differentiation,IL-6 and TGF-β are key factors for the generation of Th17 cells fromnaïve T CD4⁺ cells. On the other hand, IL-6 inhibits TGF-β-induced Tregcells which suppress adaptive T cell responses and prevent autoimmunity,and are thus important in the maintenance of immune homeostasis. The twoT-cell subsets play prominent roles in immune functions: Th17 plays akey role in the pathogenesis of autoimmune diseases and protectionagainst bacterial infections, while Treg functions to restrain excessivehelper T-cell responses. Essentially immunosuppressive Tregs cells andpro-inflammatory Th17 cells functionally antagonize each other.

As such, a fine balance between Th17 and Treg cells may be crucial forthe stability of immune homeostasis. Once the equilibrium is broken, thedestabilization may lead to chronic inflammation and autoimmunity. Forexample, dysregulation or overproduction of IL-6 leads to autoimmunediseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA),in which Th17 cells are considered to be the primary cause of pathology.Clinical evidence indicates that both defects in Treg function orreduced numbers, as well as Th17 activity are important in severalautoimmune diseases, including seronegative arthritis in adults, andchildhood arthritis (juvenile idiopathic arthritis). Therefore, aneffective approach in the treatment of various autoimmune andinflammatory diseases will be to normalize the balance between Treg andTh17 cell development.

There are two main types of receptors that mediate the effects ofderivatives of vitamin A in mammals (and other organisms), the RetinoicAcid Receptors (RARs) and the Retinoid X Receptors (RXRs). Within eachtype there are three subtypes designated RAR alpha, RAR beta, and RARgamma for the RAR family and RXR alpha, RXR beta, and RXR gamma for theRXR family. These receptor types are evolutionarily related but arefunctionally distinct. The ligands that activate the RARs, referred toas retinoids, and the ligands that activate the RXRs, referred to asrexinoids, elicit quite different biological effects. Retinoic acid(RA), the physiological hormone of all three RARs, has been shown toenhance the in vitro differentiation of Treg cells that suppressimmunity. RA can also inhibit the differentiation of pro-inflammatoryTh17 cells that have been casually implicated in the development of manyhuman autoimmune diseases. Based on this ability to restore a normalTh17/Treg cell ratio by decreasing Th17 cells while simultaneouslyincreasing Treg cells, RAR agonists have been proposed as effectivetherapeutic compounds for the treatment of inflammatory and autoimmunedisorders. However, recent findings have identified retinoid signalingthrough RARs as being required for the initial development of Th17 cellmediated immune responses and inflammation. These counteracting effectsof RAR pan agonists on Th17 cell development bring into question thevalue of such compounds as anti-inflammatory and immunosuppressiveagents.

Although RAR agonists like retinoic acid have been used to treatautoimmune disorders associated with inflammation, their usefulness inclinical practice has been limited due to unwanted side effects andcounter-therapeutic inflammatory effects. Thus, what are needed arecompounds and compositions that maintain the ability to inhibit Th17cell formation and function and to promote Treg cell formation, but notpossess any pro-inflammatory activities and other unwanted side effectsassociated with RAR pan agonists like RA. Such compounds will be ofconsiderable therapeutic value as immunomodulatory agents.

RXRs function as ligand-activated nuclear receptors which regulate thetranscription of target genes. RXRs can form RXR homodimers and also canform heterodimers with a range of other nuclear receptors. These RXRheterodimers fall into two broad classes; non-permissive heterodimerswith receptors such as RAR, vitamin D receptor (VDR), and thyroidhormone receptor (TR) and permissive heterodimers with receptors such asperoxisome proliferator activator receptor (PPAR), farnesoid X receptor(FXR), and liver X receptor (LXR). The non-permissive RXR heterodimerssuch as RXR/RAR cannot be activated by RXR ligands but only by ligandsto the partner receptor (e.g.: RAR). However, the permissiveheterodimers can be activated by both ligands to RXR as well as ligandsto the partner receptor (e.g.: PPAR).

SUMMARY

The present specification discloses compounds, compositions, and methodsfor treating an individual suffering from an autoimmune disorder, inparticular a demyelination-related disorder. This is accomplished byadministering a therapeutically effective amount of a RXR agonist orcomposition comprising such agonist to an individual suffering from anautoimmune disorder, in particular a demyelination-related disorder. Asdisclosed herein, the disclosed RXR agonists can control the Th17/Tregcell number ratio by elevating Treg cell numbers and suppressing Th17cell numbers and also promote remyelination. As such, the disclosed RXRagonists would be useful in treating an autoimmune disorder, inparticular a demyelination-related disorder.

Thus, disclosed herein is a method of treating a demyelination-relateddisorder, the method comprising the step of administering to anindividual in need thereof a therapeutically effective amount of a RXRagonist with both remyelination promotion and immunomodulatoryactivities, wherein administration of the RXR agonist treats thedemyelination-related disorder in the individual by both promotingremyelination of neurons and modulating the individual's immune system.

In one embodiment, the immunomodulatory activity comprises increasingthe number of Treg cells in the individual. In another embodiment, theimmunomodulatory activity comprises decreasing the number of Th17 cellsin the individual. In yet another embodiment, the immunomodulatoryactivity comprises increasing the number of Treg cells and decreasingthe number of Th17 cells in the individual.

Thus, aspects of the present specification disclose a RXR agonist.Non-limiting examples of a RXR agonist include a compound having thestructure of formula I,

wherein Z is a radical having the structure of Formula II:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹═CR¹═CR¹)— groups on adjacent carbons; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, R¹³ is divalent alkyl radical of 2-5carbons; and n is 1 or 2.

In another embodiment, the demyelination-related disorder is a centralnervous system disorder and the central nervous system disorder ismultiple sclerosis, neuromyelitis optica, acute disseminatedencephalomyelitis, Marburg multiple sclerosis, diffuse myelinoclasticsclerosis (Schilder's disease), Balo concentric sclerosis, solitarysclerosis, optic neuritis, transverse myelitis, amyotrophic lateralsclerosis, leukodystrophy (multiple variants, e.g. adrenoleukodystrophy,adrenomyeloneuropathy), Parkinson's disease, Alzheimer's disease,progressive supranuclear palsy, stroke, traumatic brain injury,radiation induced neuroinflammation, radiation-induced central nervoussystem inflammation, radiation somnolence syndrome, Devic's disease,inflammatory demyelinating diseases, a CNS neuropathies like thoseproduced by vitamin B12 deficiency, central pontine myelinolysis,myelopathies like Tabes dorsalis (syphilitic myelopathy),leukoencephalopathies like progressive multifocal leukoencephalopathy,or leukodystrophies.

In another embodiment, the demyelination-related disorder is aperipheral nervous system disorder such as Guillain-Barré Syndrome,acute inflammatory demyelinating polyneuropathy, chronic inflammatorydemyelinating polyneuropathy, demyelinating diabetic neuropathy,progressive inflammatory neuropathy, drug- or toxin-induced neuropathy,such as chemotherapy-induced neuropathy or organophosphate-inducedneuropathy, anti-MAG peripheral neuropathy, Charcot-Marie-Tooth Disease,or copper deficiency.

In another embodiment, the therapeutically effective amount is about0.001 mg/kg/day to about 100 mg/kg/day, or about 0.1 mg/kg/day to about10 mg/kg/day. In yet another embodiment, the therapeutically effectiveamount is about 0.01 mg/m²/day to about 100 mg/m²/day or about 15mg/m²/day to about 60 mg/m²/day.

In certain embodiments, the RXR agonist is administered by nasaladministration.

In another embodiment, treatment with the RXR agonist reduces at leastone symptom of the demyelination-related disorder, wherein at least onesymptom reduced is inflammation, fatigue, dizziness, malaise, elevatedfever and high body temperature, extreme sensitivity to cold in thehands and feet, weakness and stiffness in muscles and joints, weightchanges, digestive or gastrointestinal problems, low or high bloodpressure, irritability, anxiety, or depression, blurred or doublevision, ataxia, clonus, dysarthria, fatigue, clumsiness, hand paralysis,hemiparesis, genital anesthesia, incoordination, paresthesias, ocularparalysis, impaired muscle coordination, weakness (muscle), loss ofsensation, impaired vision, neurological symptoms, unsteady gait,spastic paraparesis, incontinence, hearing problems, or speech problems.

Also disclosed herein is a method of treating multiple sclerosis, themethod comprising the step of administering to an individual in needthereof a therapeutically effective amount of a RXR agonist, wherein theRXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid; and wherein administration of the RXR agonist reducesa symptom associated with the multiple sclerosis, thereby treating theindividual.

Also disclosed herein is a method of treating radiation-induced centralnervous system (CNS) inflammation, the method comprising the step ofadministering to an individual in need thereof a therapeuticallyeffective amount of a RXR agonist, wherein the RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid; and wherein administration of the RXR agonist reducesa symptom associated with the radiation-induced CNS inflammation,thereby treating the individual.

Also disclosed herein is a method of treating a CNSdemyelination-related disorder, the method comprising the step ofadministering to an individual in need thereof a therapeuticallyeffective amount of a RXR agonist, wherein the RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid; and wherein administration of the RXR agonist reducesa symptom associated with the CNS demyelination-related disorder,thereby treating the individual and wherein the RXR agonists isdelivered directly to the CNS of the individual by intrathecaladministration, epidural administration, cranial injection or implant,or nasal administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A-B shows that RXR agonists regulate Foxp3 (FIG. 1A) and α4β7(FIG. 1B) expression.

FIG. 2A-B shows that RXR agonists increase Treg differentiation underTh17 conditions (FIG. 2A) and inhibit Th17 differentiation under Th17conditions (FIG. 2B).

FIG. 3 shows the effects of RAR signaling inhibition on RXR agonistinducement of Treg differentiation.

FIG. 4 shows RXR agonist activation of transcription from RXRα, RXRβ,RXRγ, RARα, RARβ, and RARγ using transactivation assays.

FIG. 5 shows that RXR agonists attenuate experimental autoimmuneencephalomyelitis (EAE) in C57BL/6 mice.

FIG. 6A-B shows that RXR agonists reduce leukocyte infiltration into thecentral nervous system. FIG. 6A depicts the number of CD4⁺ cells andFIG. 6B depicts the number of CD11c⁺ CD11b⁺ cells (myeloid DC) in micetreated with the RXR agonist IRX4204 (4204) verses the vehicle control.

FIG. 7 shows RXR agonists attenuate EAE in SJL mice.

FIG. 8A-D shows that IRX4204 selectively activates RXR-Nurr1heterodimers. Transactivation assay of IRX4204 (194204, Formula XXIX)for farnesoid X receptor FXR (FIG. 8A); for liver X receptors LXRα andLXRβ (FIG. 8B); for peroxisome proliferator-activated receptor PPARγ(FIG. 8C); and for Nurr1 receptor in the presence or absence of RXR(FIG. 8D).

FIG. 9 shows the percentage of green fluorescent protein (EGFP) positiveoligodendrocytes after culture of oligodendrocyte precursor cellsderived from embryonic mouse brains with various concentrations ofIRX4204.

FIG. 10 depicts effects of RXR agonist IRX4204 on EAE in mice,

FIG. 11A-B depicts expression of CCR6 (FIG. 11A) and CD49d (FIG. 11B) onsplenocytes from EAE mice treated with 200 μg/day of IRX4204 or control.

FIG. 12A-D depicts quantification (FIG. 12A) and frequency (FIG. 12B) ofCD4+CD25hi cells, total number of effector and memory CD4 T cells (FIG.12C), and total number of activated CD4 T cells (FIG. 12D) insplenocytes from EAE mice treated with 200 μg/day of IRX4204 or control.

FIG. 13 depicts the total number of infiltrating CD4 T cells in the CNSof EAE mice treated with 200 μg/day of IRX4204 or control.

FIG. 14A-D depicts restimulation of the infiltrating lymphocytes of FIG.13 to determine expression of interferon gamma (IFNγ) (FIG. 14A), IL-17A(FIG. 14B), tumor necrosis factor (TNF) (FIG. 14C), and IL-4 (FIG. 14D).

FIG. 15A-C depicts the quantification of co-expression of IFNγ andIL-17A by CD4 T cells of FIG. 13 expressing IL-17A and not IFNγ (FIG.15A), IL-17A and IFNγ (FIG. 15B), IFNγ and not IL-17A (FIG. 15C).

DETAILED DESCRIPTION

Many diseases of the central nervous system (CNS) are associated withdemyelination of axons and neurons. Such disorders of demyelination maybe autoimmune diseases or disorders of other etiologies. MultipleSclerosis (MS) is an example of an autoimmune disorder which is alsoassociated with demyelination. Accordingly, an optimal drug for thetreatment of MS would address the autoimmune aspect of the disease whileconcurrently enhancing remyelination. MS is currently treated by severalimmunomodulatory drugs that provide clinical benefit by modulatingpatient immune responses and producing anti-inflammatory effects. Thesedrugs delay disease progression but do not reverse disease pathology orrestore neurological function by restoring myelination of damagedneurons. IRX4204 (194204, Formula XXIX), a Retinoid X Receptor (RXR)ligand that has an unique mechanism of action in being a selectiveactivator of RXR homodimers and RXR-Nurr1 heterodimers, simultaneouslyprovides immunomodulatory activities and also promotes remyelination.IRX4204 promotes the differentiation of suppressive Treg cells whilesimultaneously inhibiting the differentiation of pro-inflammatory Th17cells thereby favorably affecting the aberrantly skewed Th17/Treg cellratio which underlies human autoimmune diseases such as MS. Thus, byvirtue of its effects on Th17/Treg cell ratios, IRX4204 will haveclinical benefits similar to current standard of care treatments in MS.IRX4204 can additionally promote remyelination of demyelinated CNSneurons. Accordingly, IRX4204, and other RXR ligands of the samereceptor activating profile, compounds that provide bothimmunomodulatory activity and promote remyelination, will not only delaydisease progression in MS but also effect neural repair by regeneratinghealthy axons and neurons. IRX4204 is expected to be an optimal drug forthe treatment of MS and other autoimmune diseases which are alsoassociated with demyelination.

The RARs and RXRs and their cognate ligands function by distinctmechanisms. The RARs always form heterodimers with RXRs and theseRAR/RXR heterodimers bind to specific response elements in the promoterregions of target genes. The binding of RAR agonists to the RAR receptorof the heterodimer results in activation of transcription of targetgenes leading to retinoid effects. On the other hand, RXR agonists donot activate RAR/RXR heterodimers. RXR heterodimer complexes likeRAR/RXR, can be referred to as non-permissive RXR heterodimers asactivation of transcription due to ligand-binding occurs only at thenon-RXR protein (e.g., RAR); activation of transcription due to ligandbinding does not occur at the RXR. RXRs also interact with nuclearreceptors other than RARs and RXR agonists may elicit some of itsbiological effects by binding to such RXR/receptor complexes. TheseRXR/receptor complexes can be referred to as permissive RXR heterodimersas activation of transcription due to ligand-binding could occur at theRXR, the other receptor, or both receptors. Examples of permissive RXRheterodimers include, without limitation, peroxisome proliferatoractivated receptor/RXR (PPAR/RXR), farnesyl X receptor/RXR (FXR/RXR),nuclear receptor related-1 protein (Nurr1/RXR) and liver X receptor/RXR(LXR/RXR). Alternately, RXRs may form RXR/RXR homodimers which can beactivated by RXR agonists leading to rexinoid effects. Also, RXRsinteract with proteins other than nuclear receptors and ligand bindingto an RXR within such protein complexes can also lead to rexinoideffects. Due to these differences in mechanisms of action, RXR agonistsand RAR agonists elicit distinct biological outcomes and even in theinstances where they mediate similar biological effects, they do so bydifferent mechanisms. Moreover, the unwanted side effects of retinoids,such as pro-inflammatory responses or mucocutaneous toxicity, aremediated by activation of one or more of the RAR receptor subtypes.Stated another way, biological effects mediated via RXR pathways wouldnot induce pro-inflammatory responses, and thus, would not result inunwanted side effects.

As disclosed herein, RXR agonists inhibit Th17 cell formation andpromote Treg cell formation by mechanisms that do not involve RARs. Assuch, a selective RXR agonist that does not activate RARs would be amore effective agent in the treatment of an autoimmune disorder, inparticular a demyelination-related disorder. In support of this, thepresent specification discloses that RXR agonists have celldifferentiating effects in that they can regulate the Th17/Treg cellnumber ratio by elevating Treg cell numbers and suppressing Th17 cellnumbers. In this manner, a normal balance of both these cell types canbe achieved and immune homeostatis restored. Furthermore, sinceselective RXR agonists achieve these therapeutic effects withoutactivation of RARs, they would be optimally effective and beneficial intreating an autoimmune disorder, in particular a demyelination relateddisease.

Thus, aspects of the present specification provide, in part, a RXRagonist. As used herein, the term “RXR agonist”, is synonymous with “RXRselective agonist” and refers to a compound that selectively binds toone or more RXR receptors like a RXRα, a RXRβ, or a RXRγ in a mannerthat elicits gene transcription via an RXR response element. As usedherein, the term “selectively binds,” when made in reference to a RXRagonist, refers to the discriminatory binding of a RXR agonist to theindicated target receptor like a RXRα, a RXRβ, or a RXRγ such that theRXR agonist does not substantially bind with non-target receptors like aRARα, a RARβ or a RARγ.

In one embodiment, the selective RXR agonist does not activate to anyappreciable degree the permissive heterodimers PPAR/RXR, FXR/RXR, andLXR/RXR. In another embodiment, the RXR agonist activates the permissiveheterodimer Nurr1/RXR. One example of such a selective RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid (IRX4204, 194204, Formula XXIX) disclosed herein, thestructure of which is shown in Formula XXIX. In other aspects of thisembodiment, the RXR agonist activates the permissive heterodimersPPAR/RXR, FXR/RXR, or LXR/RXR by 1% or less, 2% or less, 3% or less, 4%or less, 5% or less, 6% or less, 7% or less, 8% or less, 9% or less, or10% or less relative to the ability of an activating RXR agonist toactivate the same permissive heterodimer. Examples of an RXR agonistwhich activates one or more of PPAR/RXR, FXR/RXR, or LXR/RXR include,e.g., LGD1069 (bexarotene) and LGD268.

IRX4204, like many other RXR ligands, does not activate non-permissiveheterodimers such as RAR/RXR. However, IRX4204 is unique in that itspecifically activates the Nurr1/RXR heterodimer and does not activateother permissive RXR heterodimers such as PPAR/RXR, FXR/RXR, andLXR/RXR. Other RXR ligands generally activate these permissive RXRheterodimers. Thus, all RXR ligands cannot be classified as belonging toone class. IRX4204 belongs to a unique class of RXR ligands whichspecifically activate RXR homodimers and only one of the permissive RXRheterodimers, namely the Nurr1/RXR heterodimer. This unique receptorprofile enables IRX4204 to have both immunomodulatory and neural repairproperties. Thus, the use of specific RXR homodimer, Nurr1/RXRactivators, such as IRX4204, provides a uniquely effective ways oftreating demyelination-related disorders, such as multiple sclerosis.

Selective binding of a RXR agonist to a RXR receptor includes bindingproperties such as, e.g., binding affinity and binding specificity.Binding affinity refers to the length of time a RXR agonist resides atits RXR receptor binding site, and can be viewed as the strength withwhich a RXR agonist binds its a RXR receptor. Binding affinity can bedescribed as a RXR agonist's equilibrium dissociation constant (KD),which is defined as the ratio Kd/Ka at equilibrium, where Ka is a RXRagonist's association rate constant and kd is a RXR agonist'sdissociation rate constant. Binding affinity is determined by both theassociation and the dissociation and alone neither high association norlow dissociation can ensure high affinity. The association rate constant(Ka), or on-rate constant (Kon), measures the number of binding eventsper unit time, or the propensity of a RXR agonist and its RXR receptorto associate reversibly into its agonist-receptor complex. Theassociation rate constant is expressed in M⁻¹ s⁻¹, and is symbolized asfollows: [Ag]×[Rc]×Kon. The larger the association rate constant, themore rapidly a RXR agonist binds to its RXR receptor, or the higher thebinding affinity between agonist and receptor. The dissociation rateconstant (Kd), or off-rate constant (Koff), measures the number ofdissociation events per unit time propensity of an agonist-receptorcomplex to separate (dissociate) reversibly into its componentmolecules, namely the RXR agonist and the RXR receptor. The dissociationrate constant is expressed in s⁻¹, and is symbolized as follows:[Ag+Rc]×Koff. The smaller the dissociation rate constant, the moretightly bound a RXR agonist is to its RXR receptor, or the higher thebinding affinity between agonist and receptor. The equilibriumdissociation constant (KD) measures the rate at which newagonist-receptor complexes formed equals the rate at whichagonist-receptor complexes dissociate at equilibrium. The equilibriumdissociation constant is expressed in M, and is defined asKoff/Kon=[Ag]×[Rc]/[Ag+Rc], where [Ag] is the molar concentration of aRXR agonist, [Rc] is the molar concentration of the RXR receptor, and[Ag+Rc] is the of molar concentration of the agonist-receptor complex,where all concentrations are of such components when the system is atequilibrium. The smaller the equilibrium dissociation constant, the moretightly bound a RXR agonist is to its RXR receptor, or the higher thebinding affinity between agonist and receptor.

In aspects of this embodiment, the binding affinity of a RXR agonistthat selectively binds to a RXR receptor can have an association rateconstant of, e.g., less than 1×10⁵ M⁻¹ s⁻¹, less than 1×10⁶ M⁻¹ s⁻¹,less than 1×10⁷ M⁻¹ s⁻¹, or less than 1×10⁸ M⁻¹ s⁻¹. In anotherembodiment, the binding affinity of a RXR agonist that selectively bindsto a RXR receptor can have an association rate constant of, e.g., morethan 1×10⁵ M⁻¹ s⁻¹, more than 1×10⁶ M⁻¹ s⁻¹, more than 1×10⁷ M⁻¹ s⁻¹, ormore than 1×10⁸ M⁻¹ s⁻¹. In other aspects, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an associationrate constant between, e.g., 1×10⁵ M⁻¹ s⁻¹ to 1×10⁸ M⁻¹ s⁻¹, 1×10⁶ M⁻¹s⁻¹ to 1×10⁸ M⁻¹ s⁻¹, 1×10⁵ M⁻¹ s⁻¹ to 1×10⁷ M⁻¹ s⁻¹, or 1×10⁶ M⁻¹ s⁻¹to 1×10⁷ M⁻¹ s⁻¹.

In other aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have adisassociation rate constant of, e.g., less than 1×10⁻³ s⁻¹, less than1×10⁻⁴ s⁻¹, or less than 1×10⁻⁵ s⁻¹. In another embodiment, the bindingaffinity of a RXR agonist that selectively binds to a RXR receptor canhave a disassociation rate constant of, e.g., more than 1×10⁻³ s⁻¹, morethan 1×10⁻⁴ s⁻¹, or more than 1×10⁻⁵ s⁻¹. In other aspects, the bindingaffinity of a RXR agonist that selectively binds to a RXR receptor canhave a disassociation rate constant between, e.g., 1×10⁻³ s⁻¹ to 1×10⁻⁵s⁻¹, 1×10⁻³ s⁻¹ to 1×10⁻⁴ s⁻¹, or 1×10⁻⁴ s⁻¹ to 1×10⁻⁵ s⁻¹.

In yet other aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an equilibriumdisassociation constant of less than 100 nM. In aspects of thisembodiment, the binding affinity of a RXR agonist that selectively bindsto a RXR receptor can have an equilibrium disassociation constant of,e.g., less than 100 nM, less than 90 nM, less than 80 nM, less than 70nM, less than 60 nM, less than 50 nM, less than 40 nM, less than 30 nM,less than 20 nM, or less than 10 nM. In aspects of this embodiment, thebinding affinity of a RXR agonist that selectively binds to a RXRreceptor can have an equilibrium disassociation between, e.g., 0.1 nM to10 nM, 0.1 nM to 50 nM, 0.1 nM to 100 nM, 0.5 nM to 10 nM, 0.5 nM to 50nM, 0.5 nM to 100 nM, 1 nM to 10 nM, 1 nM to 50 nM, or 1 nM to 100 nM.

In still other aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR can have an association rateconstant for a RAR receptor of, e.g., less than 1×10⁰ M⁻¹ s⁻¹, less than1×10¹ M⁻¹ s⁻¹, less than 1×10² M⁻¹ s⁻¹, less than 1×10³ M⁻¹ s⁻¹, or lessthan 1×10⁴ M⁻¹ s⁻¹. In another embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an associationrate constant of a RAR receptor of, e.g., at most 1×10⁰ M⁻¹ s⁻¹, at most1×10¹ M⁻¹ s⁻¹, at most 1×10² M⁻¹ s⁻¹, at most 1×10³ M⁻¹ s⁻¹, or at most1×10⁴ M⁻¹ s⁻¹.

In further aspects of this embodiment, the binding affinity of a RXRagonist that selectively binds to a RXR receptor can have an equilibriumdisassociation constant for a RAR receptor of, e.g., more than 500 nM,for than 1,000 nM, more than 5,000 nm, or more than 10,000 nM. Inanother embodiment, the binding affinity of a RXR agonist thatselectively binds to a RXR receptor can have an equilibriumdisassociation constant for a RAR receptor between, e.g., 500 nM to10,000 nM, 1,000 nM to 10,000 nM, or 5,000 nM to 10,000 nM.

Binding specificity is the ability of a RXR agonist to discriminatebetween a RXR receptor and a receptor that does not contain its bindingsite, such as, e.g., a RAR receptor. One way to measure bindingspecificity is to compare the Kon association rate of a RXR agonist forits RXR relative to the Kon association rate of a RXR agonist for areceptor that does not contain its binding site. For example, comparingthe Ka of a RXR agonist for its RXR receptor relative to a RAR receptor

In aspects of this embodiment, a RXR agonist that selectively binds to aRXR receptor can have a Ka for a receptor not comprising its bindingsite of, e.g., less than 1×10⁰ M⁻¹ s⁻¹, less than 1×10¹ M⁻¹ s⁻¹, lessthan 1×10² M⁻¹ s⁻¹, less than 1×10³ M⁻¹ s⁻¹ or less than 1×10⁴ M⁻¹ s⁻¹.In other aspects of this embodiment, a RXR agonist that selectivelybinds to a RXR receptor can have a Ka for a receptor not comprising itsbinding site of, e.g., at most 1×10⁰ M⁻¹ s⁻¹, at most 1×10¹ M⁻¹ s⁻¹, atmost 1×10² M⁻¹ s⁻¹, at most 1×10³ M⁻¹ s⁻¹ or at most 1×10⁴ M⁻¹ s⁻¹.

In other aspects of this embodiment, a RXR agonist that selectivelybinds to a RXR receptor can have a Ka for a receptor not comprising itsbinding site of, e.g., at least 2-fold more, at least 3-fold more, atleast 4-fold more, at least 5-fold more, at least 6-fold more, at least7-fold more, at least 8-fold more, or at least 9-fold more. In furtheraspects of this embodiment, a RXR agonist that selectively binds to aRXR receptor can have a Ka for a receptor not comprising its bindingsite of, e.g., at least 10-fold more, at least 100-fold more, at least1,000-fold more or at least 10,000-fold more. In yet other aspects ofthis embodiment, a RXR agonist that selectively binds to a RXR receptorcan have a Ka for a receptor not comprising its binding site of, e.g.,at most 1-fold more, at most 2-fold more, at most 3-fold more, at most4-fold more, at most 5-fold more, at most 6-fold more, at most 7-foldmore, at most 8-fold more, or at most 9-fold more. In yet other aspectsof this embodiment, a RXR agonist that selectively binds to a RXRreceptor can have a Ka for a receptor not comprising its binding siteof, e.g., at most 10-fold more, at most 100-fold more, at most1,000-fold more or at most 10,000-fold more.

The binding specificity of a RXR agonist that selectively binds to a RXRreceptor can also be characterized as a binding ratio that such a RXRagonist can discriminate its RXR receptor relative to a receptor notcomprising its binding site, such as, e.g., a RAR receptor. In aspectsof this embodiment, a RXR agonist that selectively binds to a RXRreceptor has a binding ratio for its RXR receptor relative to a receptornot comprising its binding site of, e.g., at least 2:1, at least 3:1, atleast 4:1, at least 5:1, at least 64:1, at least 7:1, at least 8:1, atleast 9:1, at least 10:1, at least 15:1, at least 20:1, at least 25:1,at least 30:1, at least 35:1, or at least 40:1. In other aspects of thisembodiment, a RXR agonist that selectively binds to a RXR receptor has abinding ratio for its RXR receptor relative to a RAR receptor of, e.g.,at least 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1,at least 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1,at least 20:1, at least 25:1, at least 30:1, at least 35:1, or at least40:1.

In aspects of this embodiment, a RXR agonist will have a ratio ofactivity at a RXR receptor relative to a RAR receptor of, e.g., at least5 greater, at least 10 greater, at least 15, or at least 20 greater.

The binding specificity of a RXR agonist that selectively binds to a RXRreceptor can also be characterized as an activity ratio that such a RXRagonist can exert activity through binding to its RXR receptor relativeto a receptor not comprising its binding site, such as, e.g., a RARreceptor. In aspects of this embodiment, a RXR agonist that selectivelybinds to a RXR receptor has an activity ratio through its RXR receptorrelative to a receptor not comprising its binding site of, e.g., atleast 2:1, at least 3:1, at least 4:1, at least 5:1, at least 64:1, atleast 7:1, at least 8:1, at least 9:1, at least 10:1, at least 15:1, atleast 20:1, at least 25:1, at least 30:1, at least 35:1, or at least40:1. In other aspects of this embodiment, a RXR agonist thatselectively binds to a RXR receptor has an activity ratio through itsRXR receptor relative to a RAR receptor of, e.g., at least 2:1, at least3:1, at least 4:1, at least 5:1, at least 64:1, at least 7:1, at least8:1, at least 9:1, at least 10:1, at least 15:1, at least 20:1, at least25:1, at least 30:1, at least 35:1, or at least 40:1.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula I:

wherein Z is a radical having the structure of Formula II:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹═CR¹═CR¹)— groups on adjacent carbons; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, R¹³ is divalent alkyl radical of 2-5carbons; and n is 1 or 2.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula III:

wherein R² is hydrogen or lower alkyl; R³ is hydrogen or lower alkyl,and B is hydrogen, COOH or a pharmaceutically acceptable salt thereof,—COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)²,—CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, whereR⁷ is an alkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons,R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10carbons or trimethylsilylalkyl where the alkyl group has 1 to 10carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is lower alkyl,phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalentalkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula IV:

wherein n is 1 or 2; R¹ and R² independently are H, lower alkyl orfluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is H, loweralkyl, fluoroalkyl or halogen, and B is hydrogen, —COOH or apharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH,—CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)², —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂,—CR⁷OR¹³O, or trilower alkylsilyl where R⁷ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is lower alkyl,phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalentalkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula V:

where R⁴ is lower alkyl of 1 to 6 carbons; B is —COOH or —COOR⁸ where R⁹is lower alkyl of 1 to 6 carbons, and the configuration about thecyclopropane ring is cis, and the configuration about the double bondsin the pentadienoic acid or ester chain attached to the cyclopropanering is trans in each of the double bonds, or a pharmaceuticallyacceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula VI:

wherein Z is a radical having the structure of Formula VII:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹═CR¹═CR¹)— groups on adjacent carbons; X is S or O; R¹ andR² independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen,lower alkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and Bis hydrogen, —COOH or a pharmaceutically acceptable salt thereof,—COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂,—CHOR¹³O, —OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, whereR⁷ is an alkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons,R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10carbons or trimethylsilylalkyl where the alkyl group has 1 to 10carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰ independentlyare hydrogen, an alkyl group of 1 to 10 carbons, or a cycloalkyl groupof 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ is lower alkyl,phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ is divalentalkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula VIII:

wherein X is S or O; R² is hydrogen or lower alkyl; R³ is hydrogen orlower alkyl, and B is hydrogen, —COOH or a pharmaceutically acceptablesalt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,—CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or triloweralkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkylgroup of 5 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰independently are hydrogen, an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ islower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2-5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula IX:

wherein Z is a radical having the structure of Formula X:

Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups beingoptionally substituted with one or two R⁴ groups, the divalent Y radicalbeing substituted by the Z and —(CR¹═CR¹═CR¹═CR¹)— groups on adjacentcarbons; X is NR⁵; n is 1 or 2; R¹ and R² independently are H, loweralkyl or fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is loweralkyl, fluoroalkyl or halogen; R⁵ is H or lower alkyl, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O,—COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R8 isphenyl or lower alkylphenyl, R9 and R10 independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R11 is lower alkyl, phenyl or loweralkylphenyl, R12 is lower alkyl, and R13 is divalent alkyl radical of 2to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula IX:

wherein Z is a radical having the structure of Formula X:

Y is selected from pyridyl, pyrrolyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, oxazolyl, and imidazolyl, the groups beingoptionally substituted with one or two R⁴ groups, the divalent Y radicalbeing substituted by the Z and —(CR¹═CR¹═CR¹═CR¹)— groups on adjacentcarbons; X is NR⁵; n is 1 or 2; R¹ and R² independently are H, loweralkyl or fluoroalkyl; R³ is hydrogen, lower alkyl, Cl or Br; R⁴ is loweralkyl, fluoroalkyl or halogen; R⁵ is H or lower alkyl, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)², —CHOR¹³O,—COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XII:

wherein R is H, lower alkyl or 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XII:

wherein Z is a radical having the structure of Formula XIV:

Y is cyclopropyl, the Y group being optionally substituted with one ortwo R⁴ groups, the divalent Y radical being substituted by the Z and—(CR¹═CR¹═CR¹═CR¹)— groups on adjacent carbons; X is NR⁵; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or hydrogen; R⁵ is H orlower alkyl, and B is hydrogen, —COOH or a pharmaceutically acceptablesalt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,—CH(OR¹²)², —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or triloweralkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenyl group containing1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons, a cycloalkylgroup of 5 to 10 carbons or trimethylsilylalkyl where the alkyl grouphas 1 to 10 carbons, or R⁸ is phenyl or lower alkylphenyl, R⁹ and R¹⁰independently are hydrogen, an alkyl group of 1 to 10 carbons, or acycloalkyl group of 5-10 carbons, or phenyl or lower alkylphenyl, R¹¹ islower alkyl, phenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2 to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XV:

wherein X is NR⁵; R⁵ is H or lower alkyl; R² is H or lower alkyl; R³ isH or lower alkyl, and B is hydrogen, —COOH or a pharmaceuticallyacceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹,—CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O,or trilower alkylsilyl, where R⁷ is an alkyl, cycloalkyl or alkenylgroup containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkylwhere the alkyl group has 1 to 10 carbons, or R⁸ is phenyl or loweralkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl, R¹² islower alkyl, and R¹³ is divalent alkyl radical of 2 to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XVI:

where Y is a bivalent radical having the structure of Formula XVII:

the two X¹ groups jointly represent an oxo (═O) or thione (═S) function,or X¹ is independently selected from H or alkyl of 1 to 6 carbons; thetwo X² groups jointly represent an oxo (═O) or a thione (═S) function,or X² independently selected from H or alkyl of 1 to 6 carbons, with theproviso that one of the joint X¹ grouping or of the joint X² groupingrepresents an oxo (═O) or thione (═S) function; W is O, C(R¹)₂, or Wdoes not exist; R¹ is independently H, lower alkyl of 1 to 6 carbons, orlower fluoroalkyl of 1 to 6 carbons; R² is independently H, lower alkylof 1 to 6 carbons, or lower fluoroalkyl of 1 to 6 carbons; R³ ishydrogen, lower alkyl of 1 to 6 carbons, OR¹, fluoro substituted loweralkyl of 1 to 6 carbons halogen, NO₂, NH₂, —NHCO(C₁-C₆) alkyl, or—NHCO(C₁-C₆) alkenyl; A is hydrogen, —COOH or a pharmaceuticallyacceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹,—CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CH(OR¹³O), —COR⁷, —CR⁷(OR¹²)₂,—CR⁷(OR¹³O), or —Si(C₁-C₆)₃, where R⁷ is an alkyl, cycloalkyl or alkenylgroup containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbonsor (trimethylsilyl)alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R⁸ is phenyl or loweralkyphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,hydroxyphenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl radical of 2to 5 carbons, and R¹⁴ is H, alkyl of 1 to 10 carbons, fluoro-substitutedalkyl of 1 to 10 carbons, alkenyl of 2 to 10 carbons and having 1 to 3double bonds.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XVIII:

wherein R¹ is independently H, lower alkyl of 1 to 6 carbons, or lowerfluoroalkyl of 1 to 6 carbons; R¹* is hydrogen or C₁₋₆-alkyl; R²* isindependently H, lower alkyl of 1 to 6 carbons, or lower fluoroalkyl of1 to 6 carbons; R³* is hydrogen, lower alkyl of 1 to 6 carbons, fluorosubstituted lower alkyl of 1 to 6 carbons or halogen; X¹* is an oxo (═O)or a thione (═S) group; A* is hydrogen, —COOH or a pharmaceuticallyacceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, where R⁸ is an alkyl groupof 1 to 10 carbons or (trimethylsilyl)alkyl where the alkyl group has 1to 10 carbons, or a cycloalkyl group of 5 to 10 carbons, or R⁸ is phenylor lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkylgroup of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons, orphenyl, hydroxyphenyl or lower alkylphenyl, and the cyclopropyl group isattached to the 6 or 7 position of the tetrahydroquinoline moiety, andR¹⁴* is alkyl of 1 to 10 carbons or fluoro-substituted alkyl of 1 to 10carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formulae XIX, XX, or XXI:

where X is O, S, or (CR¹R¹)_(n) where n is 0, 1 or 2; Y is a bivalentradical having the structure of Formulae XXII or XXIII where o is aninteger between 1 through 4

or Y is a bivalent aryl or 5 or 6 membered heteroaryl radical having 1to 3 heteroatoms selected from N, S and O, the aryl or heteroaryl groupsbeing unsubstituted, or substituted with 1 to 3 C₁₋₆ alkyl or with 1 to3 C₁₋₆ fluoroalkyl groups with the proviso that when the compound is inaccordance with Formula II then Y is not a 5 or 6 membered ring; X¹ is Sor NH; R¹ is independently H, lower alkyl of 1 to 6 carbons, or lowerfluoroalkyl of 1 to 6 carbons; R² is independently H, lower alkyl of 1to 6 carbons, OR¹, adamantly, or lower fluoroalkyl of 1 to 6 carbons, orthe two R² groups jointly represent an oxo (═O) group with the provisothat when the compound is in accordance with Formula II then at leastone of the R² substituents is branched-chain alkyl or adamantly; R³ ishydrogen, lower alkyl of 1 to 6 carbons, OR¹, fluoro substituted loweralkyl of 1 to 6 carbons or halogen, NO₂, NH₂, —NHCO(C₁-C₆) alkyl, or—NHCO(C₁-C₆) alkenyl; A is —COOH or a pharmaceutically acceptable saltthereof, COOR⁸, —CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO,—CH(OR¹²)², —CH(OR¹³O), —COR⁷, —CR⁷(OR¹²)₂, —CR⁷(OR¹³O), or—Si(C₁₋₆alkyl)₃, where R⁷ is an alkyl, cycloalkyl or alkenyl groupcontaining 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10 carbons or(trimethylsilyl) alkyl where the alkyl group has 1 to 10 carbons, or acycloalkyl group of 5 to 10 carbons, or R⁸ is phenyl or loweralkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl,hydroxyphenyl or lower alkylphenyl, R¹² is lower alkyl, and R¹³ isdivalent alkyl radical of 2-5 carbons, and R¹⁴ is alkyl of 1 to 10carbons, fluoro-substituted alkyl of 1 to 10 carbons, alkenyl of 2 to 10carbons and having 1 to 3 double bonds, alkynyl having 2 to 10 carbonsand 1 to 3 triple bonds, carbocyclic aryl selected from the groupconsisting of phenyl, C₁-C₁₀-alkylphenyl, naphthyl,C₁-C₁₀-alkylnaphthyl, phenyl-C₁-C₁₀-alkyl, naphthyl-C₁-C₁₀ alkyl,C₁-C₁₀-alkenylphenyl having 1 to 3 double bonds, C₁-C₁₀-alkynylphenylhaving 1 to 3 triple bonds, phenyl-C₁-C₁₀ alkenyl having 1 to 3 doublebonds, phenyl-C₁-C₁₀ alkenyl having 1 to 3 triple bonds, hydroxyl alkylof 1 to 10 carbons, hydroxyalkenyl having 2 to 10 carbons and 1 to 3double bonds, hydroxyalkynyl having 2 to 10 carbons and 1 to 3 triplebonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenyl having 2 to 10carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2 to 10 carbonsand 1 to 3 triple bonds, acyloxyalkyl of 1 to 10 carbons, acyloxyalkenylhaving 2 to 10 carbons and 1 to 3 double bonds, or acyloxyalkynyl of 2to 10 carbons and 1 to 3 triple bonds where the acyl group isrepresented by —COR⁸, or R¹⁴ is a 5 or 6 membered heteroaryl grouphaving 1 to 3 heteroatoms, the heteroatoms being selected from a groupconsisting of O, S, and N, the heteroaryl group being unsubstituted orsubstituted with a C₁-C₁₀ alkyl group, with a C₁-C₁₀ fluoroalkyl group,or with halogen, and the dashed line in Formula XXII represents a bondor absence of a bond.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXIV:

wherein R is H, lower alkyl of 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXV:

wherein R is H, lower alkyl of 1 to 6 carbons, and R1 is iso-propyl ortertiary-butyl, or a pharmaceutically acceptable salt of the compound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXVI:

wherein R is H, lower alkyl of 1 to 6 carbons, and R¹ is iso-propyl,n-butyl or tertiary-butyl, or a pharmaceutically acceptable salt of thecompound.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXVII:

where X is O or S; Y is a bivalent cycloalkyl or cycloalkenyl radicaloptionally substituted with one to four R⁴ groups, the cycloalkenylradical having 5 to 6 carbons and one double bond, or Y is a bivalentaryl or 5 or 6 membered heteroaryl radical having 1 to 3 heteroatomsselected from N, S and O, the aryl or heteroaryl groups optionallysubstituted with 1 to 4 R⁴ groups with the proviso that the cycloalkylor the cycloalkenyl radical is not substituted on the same carbon withthe condensed cyclic moiety and with the diene containing moiety; R¹ isindependently H, alkyl of 1 to 6 carbons, or fluoroalkyl of 1 to 6carbons; R² is independently H, alkyl of 1 to 8 carbons, or fluoroalkylof 1 to 8 carbons; R¹² is independently H, alkyl of 1 to 8 carbons, orfluoroalkyl of 1 to 8 carbons; R³ is hydrogen, alkyl of 1 to 10 carbons,fluoro substituted alkyl of 1 to 10 carbons, halogen, alkoxy of 1 to 10carbons, or alkylthio of 1 to 10 carbons; NO₂, NH₂, —NHCO(C₁-C₆) alkyl,—NHCO(C₁-C₆) alkenyl, —NR¹H or N(R¹)₂, benzyloxy, C₁-C₆alkyl-substituted benzyloxy, or R³ is selected from the groups shownbelow:

R⁴ is H, halogen, alkyl of 1 to 10 carbons, fluoro substituted alkyl of1 to 6 carbons, alkoxy of 1 to 10 carbons, or alkylthio of 1 to 10carbons; m is an integer having the values of 0 to 3; r is an integerhaving the values of 1 to 10; s is an integer having the values 1 to 4;t is an integer having the values 1 to 5;

represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatomsselected from the group consisting of N, S and O; B is hydrogen, COOH ora pharmaceutically acceptable salt thereof, —COOR⁸, —CONR⁹R¹⁰, —CH₂OH,—CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)₂, —CHOR¹³O, —COR⁷, —CR⁷(OR¹²)₂,—CR⁷OR¹³O, or trilower alkylsilyl, where R⁷ is an alkyl, cycloalkyl oralkenyl group containing 1 to 5 carbons, R⁸ is an alkyl group of 1 to 10carbons, a cycloalkyl group of 5 to 10 carbons or trimethylsilylalkylwhere the alkyl group has 1 to 10 carbons, or R⁸ is phenyl or loweralkylphenyl, R⁹ and R¹⁰ independently are hydrogen, an alkyl group of 1to 10 carbons, or a cycloalkyl group of 5-10 carbons, or phenyl or loweralkylphenyl, R¹¹ is lower alkyl, phenyl or lower alkylphenyl, R¹² islower alkyl, and R¹³ is divalent alkyl radical of 2 to 5 carbons.

In an aspect of this embodiment, a RXR agonist is a compound having thestructure of formula XXVIII:

wherein R¹ is H or methyl; R⁹ is H, alkyl of 1 to 6 carbons, or apharmaceutically acceptable cation, and R³ is hydrogen, alkyl of 1 to 10carbons, halogen, alkoxy of 1 to 10 carbons, or R³ is selected from thegroups shown below:

where R⁴ is H, halogen, alkyl of 1 to 10 carbons, carbons, alkoxy of 1to 10; r is an integer having the values of 1 to 10; s is an integerhaving the values 1 to 4;

represents a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatomsselected from the group consisting of N, S and O, and t is an integerhaving the values 1 to 5.

In an aspect of this embodiment, a RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid, and has the structure of formula XXIX:

Aspects of the present specification provide, in part, a RXR agonisthaving activity that promotes Treg cell differentiation. In aspects ofthis embodiment, a RXR agonist promotes Treg cell differentiation by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%. In otheraspects of this embodiment, a RXR agonist promotes Treg celldifferentiation by about 10% to about 25%, about 10% to about 50%, about10% to about 75%, about 10% to about 100%, about 10% to about 200%,about 10% to about 300%, about 10% to about 400%, about 10% to about500%, about 25% to about 50%, about 25% to about 75%, about 25% to about100%, about 25% to about 200%, about 25% to about 300%, about 25% toabout 400%, about 25% to about 500%, about 50% to about 100%, about 50%to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%.

In an embodiment, a RXR agonist has activity that results in increasedFoxp3 expression in cells exposed to the RXR agonist. In aspects of thisembodiment, a RXR agonist increases Foxp3 expression in cells by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%, relative tocells not exposed to the same RXR agonist. In other aspects of thisembodiment, a RXR agonist increases Foxp3 expression in cells by about10% to about 25%, about 10% to about 50%, about 10% to about 75%, about10% to about 100%, about 10% to about 200%, about 10% to about 300%,about 10% to about 400%, about 10% to about 500%, about 25% to about50%, about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to cells not exposed to the same RXR agonist. In oneembodiment, the cells are naïve CD4⁺ CD25⁻ FoxP3⁻ cells cultured underTreg cell differentiation conditions.

In an embodiment, a RXR agonist has activity that results in increasedα4β7 expression in cells exposed to the RXR agonist. In aspects of thisembodiment, a RXR agonist increases α4β7 expression in cells by at least10%, at least 20%, at least 30%, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, at least 90%, at least 100%, at least200%, at least 300%, at least 400%, or at least 500%, relative to cellsnot exposed to the same RXR agonist. In other aspects of thisembodiment, a RXR agonist increases α4β7 expression in cells by about10% to about 25%, about 10% to about 50%, about 10% to about 75%, about10% to about 100%, about 10% to about 200%, about 10% to about 300%,about 10% to about 400%, about 10% to about 500%, about 25% to about50%, about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to cells not exposed to the same RXR agonist. In oneembodiment, the cells are naïve CD4⁺ CD25⁻ FoxP3⁻ cells cultured underTreg cell differentiation conditions.

Aspects of the present specification provide, in part, a RXR agonisthaving activity that inhibits Th17 cell differentiation. In aspects ofthis embodiment, a RXR agonist inhibits Th17 cell differentiation by atleast 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%. In otheraspects of this embodiment, a RXR agonist inhibits Th17 celldifferentiation by about 10% to about 25%, about 10% to about 50%, about10% to about 75%, about 10% to about 100%, about 10% to about 200%,about 10% to about 300%, about 10% to about 400%, about 10% to about500%, about 25% to about 50%, about 25% to about 75%, about 25% to about100%, about 25% to about 200%, about 25% to about 300%, about 25% toabout 400%, about 25% to about 500%, about 50% to about 100%, about 50%to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%.

In an embodiment, a RXR agonist has activity that results in decreasedIL-17A expression in cells exposed to the RXR agonist. In aspects ofthis embodiment, a RXR agonist decreases IL-17A expression in cells byat least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90%, at least 100%, atleast 200%, at least 300%, at least 400%, or at least 500%, relative tocells not exposed to the same RXR agonist. In other aspects of thisembodiment, a RXR agonist decreases IL-17A expression in cells by about10% to about 25%, about 10% to about 50%, about 10% to about 75%, about10% to about 100%, about 10% to about 200%, about 10% to about 300%,about 10% to about 400%, about 10% to about 500%, about 25% to about50%, about 25% to about 75%, about 25% to about 100%, about 25% to about200%, about 25% to about 300%, about 25% to about 400%, about 25% toabout 500%, about 50% to about 100%, about 50% to about 200%, about 50%to about 300%, about 50% to about 400%, or about 50% to about 500%,relative to cells not exposed to the same RXR agonist. In oneembodiment, the cells are naïve CD4⁺ CD25⁻ FoxP3⁻ cells cultured underTreg cell differentiation conditions.

Aspects of the present specification provide, in part, a RXR agonisthaving activity that both promotes Treg cell differentiation andinhibits Th17 cell differentiation. In aspects of this embodiment, a RXRagonist promotes Treg cell differentiation by at least 10%, at least20%, at least 30%, at least 40%, at least 50%, at least 60%, at least70%, at least 80%, at least 90%, at least 100%, at least 200%, at least300%, at least 400%, or at least 500% as well as inhibits Th17 celldifferentiation by at least 10%, at least 20%, at least 30%, at least40%, at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 100%, at least 200%, at least 300%, at least 400%, or atleast 500%. In other aspects of this embodiment, a RXR agonist promotesTreg cell differentiation by about 10% to about 25%, about 10% to about50%, about 10% to about 75%, about 10% to about 100%, about 10% to about200%, about 10% to about 300%, about 10% to about 400%, about 10% toabout 500%, about 25% to about 50%, about 25% to about 75%, about 25% toabout 100%, about 25% to about 200%, about 25% to about 300%, about 25%to about 400%, about 25% to about 500%, about 50% to about 100%, about50% to about 200%, about 50% to about 300%, about 50% to about 400%, orabout 50% to about 500%, as well as inhibits Th17 cell differentiationby about 10% to about 25%, about 10% to about 50%, about 10% to about75%, about 10% to about 100%, about 10% to about 200%, about 10% toabout 300%, about 10% to about 400%, about 10% to about 500%, about 25%to about 50%, about 25% to about 75%, about 25% to about 100%, about 25%to about 200%, about 25% to about 300%, about 25% to about 400%, about25% to about 500%, about 50% to about 100%, about 50% to about 200%,about 50% to about 300%, about 50% to about 400%, or about 50% to about500%.

In an embodiment, a RXR agonist has activity that results in increasedFoxP3 and/or α4β7 expression as well as decreases IL-17A expression incells exposed to the RXR agonist. In aspects of this embodiment, a RXRagonist increases FoxP3 and/or α4β7 expression in cells by at least 10%,at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, atleast 70%, at least 80%, at least 90%, at least 100%, at least 200%, atleast 300%, at least 400%, or at least 500%, as well as decreases IL-17Aexpression in cells by at least 10%, at least 20%, at least 30%, atleast 40%, at least 50%, at least 60%, at least 70%, at least 80%, atleast 90%, at least 100%, at least 200%, at least 300%, at least 400%,or at least 500%, relative to cells not exposed to the same RXR agonist.In other aspects of this embodiment, a RXR agonist increases FoxP3and/or α4β7 expression in cells by about 10% to about 25%, about 10% toabout 50%, about 10% to about 75%, about 10% to about 100%, about 10% toabout 200%, about 10% to about 300%, about 10% to about 400%, about 10%to about 500%, about 25% to about 50%, about 25% to about 75%, about 25%to about 100%, about 25% to about 200%, about 25% to about 300%, about25% to about 400%, about 25% to about 500%, about 50% to about 100%,about 50% to about 200%, about 50% to about 300%, about 50% to about400%, or about 50% to about 500%, as well as decreases IL-17A expressionin cells by about 10% to about 25%, about 10% to about 50%, about 10% toabout 75%, about 10% to about 100%, about 10% to about 200%, about 10%to about 300%, about 10% to about 400%, about 10% to about 500%, about25% to about 50%, about 25% to about 75%, about 25% to about 100%, about25% to about 200%, about 25% to about 300%, about 25% to about 400%,about 25% to about 500%, about 50% to about 100%, about 50% to about200%, about 50% to about 300%, about 50% to about 400%, or about 50% toabout 500%, relative to cells not exposed to the same RXR agonist.

In yet other aspects of this embodiment, a RXR agonist increasesmyelination in the central or peripheral nervous system by at leastabout 10% to at least about 25%, at least about 10% to at least about50%, at least about 10% to at least about 75%, at least about 10% to atleast about 100%, at least about 10% to at least about 200%, at leastabout 10% to at least about 300%, at least about 10% to at least about400%, at least about 10% to at least about 500%, at least about 25% toat least about 50%, at least about 25% to at least about 75%, at leastabout 25% to at least about 100%, at least about 25% to at least about200%, at least about 25% to at least about 300%, at least about 25% toat least about 400%, at least about 25% to at least about 500%, at leastabout 50% to at least about 100%, at least about 50% to at least about200%, at least about 50% to at least about 300%, at least about 50% toat least about 400%, or at least about 50% to at least about 500%,relative to myelination levels in the absence of treatment with the RXRagonist.

In yet other aspects of this embodiment, a RXR agonist increasesdifferentiation of oligodendrocyte progenitor cell differentiation intooligodendrocytes in the central or peripheral nervous system by at leastabout 10% to at least about 25%, at least about 10% to at least about50%, at least about 10% to at least about 75%, at least about 10% to atleast about 100%, at least about 10% to at least about 200%, at leastabout 10% to at least about 300%, at least about 10% to at least about400%, at least about 10% to at least about 500%, at least about 25% toat least about 50%, at least about 25% to at least about 75%, at leastabout 25% to at least about 100%, at least about 25% to at least about200%, at least about 25% to at least about 300%, at least about 25% toat least about 400%, at least about 25% to at least about 500%, at leastabout 50% to at least about 100%, at least about 50% to at least about200%, at least about 50% to at least about 300%, at least about 50% toat least about 400%, or at least about 50% to at least about 500%,relative to differentiation levels in the absence of treatment with theRXR agonist.

In yet another aspect of the present specification, a RXR agonistincreases the rate of myelin repair in the central nervous system by atleast about 10% to at least about 25%, at least about 10% to at leastabout 50%, at least about 10% to at least about 75%, at least about 10%to at least about 100%, at least about 10% to at least about 200%, atleast about 10% to at least about 300%, at least about 10% to at leastabout 400%, at least about 10% to at least about 500%, at least about25% to at least about 50%, at least about 25% to at least about 75%, atleast about 25% to at least about 100%, at least about 25% to at leastabout 200%, at least about 25% to at least about 300%, at least about25% to at least about 400%, at least about 25% to at least about 500%,at least about 50% to at least about 100%, at least about 50% to atleast about 200%, at least about 50% to at least about 300%, at leastabout 50% to at least about 400%, or at least about 50% to at leastabout 500%, relative to myelin repair rates in the absence of treatmentwith the RXR agonist.

Aspects of the present specification provide, in part, a compositioncomprising a RXR agonist. A RXR agonist includes the compounds disclosedherein. The compositions disclosed herein may, or may not, comprise anynumber and combination of compounds disclosed herein. For instance, acomposition can comprise, e.g., two or more compounds disclosed herein,three or more compounds disclosed herein, four or more compoundsdisclosed herein, or five or more compounds disclosed herein.

A compound disclosed herein, or a composition comprising such acompound, is generally administered to an individual as a pharmaceuticalcomposition. Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound as disclosedherein, or a pharmaceutically acceptable acid addition salt thereof, asan active ingredient, with conventional acceptable pharmaceuticalexcipients, and by preparation of unit dosage forms suitable fortherapeutic use. As used herein, the term “pharmaceutical composition”refers to a therapeutically effective concentration of an activecompound, such as, e.g., any of the compounds disclosed herein.Preferably, the pharmaceutical composition does not produce an adverse,allergic, or other untoward or unwanted reaction when administered to anindividual. A pharmaceutical composition disclosed herein is useful formedical and veterinary applications. A pharmaceutical composition may beadministered to an individual alone, or in combination with othersupplementary active compounds, agents, drugs or hormones. Thepharmaceutical compositions may be manufactured using any of a varietyof processes, including, without limitation, conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping, and lyophilizing. The pharmaceuticalcomposition can take any of a variety of forms including, withoutlimitation, a sterile solution, suspension, emulsion, lyophilizate,tablet, pill, pellet, capsule, powder, syrup, elixir, or any otherdosage form suitable for administration.

A pharmaceutical composition produced using the methods disclosed hereinmay be a liquid formulation, semi-solid formulation, or a solidformulation. A formulation disclosed herein can be produced in a mannerto form one phase, such as, e.g., an oil or a solid. Alternatively, aformulation disclosed herein can be produced in a manner to form twophase, such as, e.g., an emulsion. A pharmaceutical compositiondisclosed herein intended for such administration may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions.

Liquid formulations suitable for parenteral injection or for nasalsprays may comprise physiologically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions and sterilepowders for reconstitution into sterile injectable solutions ordispersions. Formulations suitable for nasal administration may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (propylene glycol, polyethyleneglycol (PEG), glycerol,and the like), suitable mixtures thereof, vegetable oils (such as oliveoil) and injectable organic esters such as ethyl oleate. Proper fluiditycan be maintained, for example, by the use of a coating such aslecithin, by the maintenance of the required particle size in the caseof dispersions and by the use of surfactants.

Pharmaceutical formulations suitable for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Semi-solid formulations suitable for topical administration include,without limitation, ointments, creams, salves, and gels. In such solidformulations, the active compound may be admixed with at least one inertcustomary excipient (or carrier) such as, a lipid and/or polyethyleneglycol.

Solid formulations suitable for oral administration include capsules,tablets, pills, powders and granules. In such solid formulations, theactive compound may be admixed with at least one inert customaryexcipient (or carrier) such as sodium citrate or dicalcium phosphate or(a) fillers or extenders, as for example, starches, lactose, sucrose,glucose, mannitol and silicic acid, (b) binders, as for example,carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,sucrose and acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain complex silicates andsodium carbonate, (e) solution retarders, as for example, paraffin, (f)absorption accelerators, as for example, quaternary ammonium compounds,(g) wetting agents, as for example, cetyl alcohol and glycerolmonostearate, (h) adsorbents, as for example, kaolin and bentonite, and(i) lubricants, as for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate or mixturesthereof. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents.

In liquid and semi-solid formulations, a concentration of a therapeuticcompound disclosed herein typically may be between about 50 mg/mL toabout 1,000 mg/mL. In aspects of this embodiment, a therapeuticallyeffective amount of a therapeutic compound disclosed herein may be from,e.g., about 50 mg/mL to about 100 mg/mL, about 50 mg/mL to about 200mg/mL, about 50 mg/mL to about 300 mg/mL, about 50 mg/mL to about 400mg/mL, about 50 mg/mL to about 500 mg/mL, about 50 mg/mL to about 600mg/mL, about 50 mg/mL to about 700 mg/mL, about 50 mg/mL to about 800mg/mL, about 50 mg/mL to about 900 mg/mL, about 50 mg/mL to about 1,000mg/mL, about 100 mg/mL to about 200 mg/mL, about 100 mg/mL to about 300mg/mL, about 100 mg/mL to about 400 mg/mL, about 100 mg/mL to about 500mg/mL, about 100 mg/mL to about 600 mg/mL, about 100 mg/mL to about 700mg/mL, about 100 mg/mL to about 800 mg/mL, about 100 mg/mL to about 900mg/mL, about 100 mg/mL to about 1,000 mg/mL, about 200 mg/mL to about300 mg/mL, about 200 mg/mL to about 400 mg/mL, about 200 mg/mL to about500 mg/mL, about 200 mg/mL to about 600 mg/mL, about 200 mg/mL to about700 mg/mL, about 200 mg/mL to about 800 mg/mL, about 200 mg/mL to about900 mg/mL, about 200 mg/mL to about 1,000 mg/mL, about 300 mg/mL toabout 400 mg/mL, about 300 mg/mL to about 500 mg/mL, about 300 mg/mL toabout 600 mg/mL, about 300 mg/mL to about 700 mg/mL, about 300 mg/mL toabout 800 mg/mL, about 300 mg/mL to about 900 mg/mL, about 300 mg/mL toabout 1,000 mg/mL, about 400 mg/mL to about 500 mg/mL, about 400 mg/mLto about 600 mg/mL, about 400 mg/mL to about 700 mg/mL, about 400 mg/mLto about 800 mg/mL, about 400 mg/mL to about 900 mg/mL, about 400 mg/mLto about 1,000 mg/mL, about 500 mg/mL to about 600 mg/mL, about 500mg/mL to about 700 mg/mL, about 500 mg/mL to about 800 mg/mL, about 500mg/mL to about 900 mg/mL, about 500 mg/mL to about 1,000 mg/mL, about600 mg/mL to about 700 mg/mL, about 600 mg/mL to about 800 mg/mL, about600 mg/mL to about 900 mg/mL, or about 600 mg/mL to about 1,000 mg/mL.

In semi-solid and solid formulations, an amount of a therapeuticcompound disclosed herein typically may be between about 0.01% to about45% by weight. In aspects of this embodiment, an amount of a therapeuticcompound disclosed herein may be from, e.g., about 0.1% to about 45% byweight, about 0.1% to about 40% by weight, about 0.1% to about 35% byweight, about 0.1% to about 30% by weight, about 0.1% to about 25% byweight, about 0.1% to about 20% by weight, about 0.1% to about 15% byweight, about 0.1% to about 10% by weight, about 0.1% to about 5% byweight, about 1% to about 45% by weight, about 1% to about 40% byweight, about 1% to about 35% by weight, about 1% to about 30% byweight, about 1% to about 25% by weight, about 1% to about 20% byweight, about 1% to about 15% by weight, about 1% to about 10% byweight, about 1% to about 5% by weight, about 5% to about 45% by weight,about 5% to about 40% by weight, about 5% to about 35% by weight, about5% to about 30% by weight, about 5% to about 25% by weight, about 5% toabout 20% by weight, about 5% to about 15% by weight, about 5% to about10% by weight, about 10% to about 45% by weight, about 10% to about 40%by weight, about 10% to about 35% by weight, about 10% to about 30% byweight, about 10% to about 25% by weight, about 10% to about 20% byweight, about 10% to about 15% by weight, about 15% to about 45% byweight, about 15% to about 40% by weight, about 15% to about 35% byweight, about 15% to about 30% by weight, about 15% to about 25% byweight, about 15% to about 20% by weight, about 20% to about 45% byweight, about 20% to about 40% by weight, about 20% to about 35% byweight, about 20% to about 30% by weight, about 20% to about 25% byweight, about 25% to about 45% by weight, about 25% to about 40% byweight, about 25% to about 35% by weight, or about 25% to about 30% byweight.

A pharmaceutical composition disclosed herein can optionally include apharmaceutically acceptable carrier that facilitates processing of anactive compound into pharmaceutically acceptable compositions. As usedherein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for contact withthe tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem complicationscommensurate with a reasonable benefit/risk ratio. As used herein, theterm “pharmacologically acceptable carrier” is synonymous with“pharmacological carrier” and refers to any carrier that hassubstantially no long term or permanent detrimental effect whenadministered and encompasses terms such as “pharmacologically acceptablevehicle, stabilizer, diluent, additive, auxiliary, or excipient.” Such acarrier generally is mixed with an active compound or permitted todilute or enclose the active compound and can be a solid, semi-solid, orliquid agent. It is understood that the active compounds can be solubleor can be delivered as a suspension in the desired carrier or diluent.Any of a variety of pharmaceutically acceptable carriers can be usedincluding, without limitation, aqueous media such as, e.g., water,saline, glycine, hyaluronic acid and the like; solid carriers such as,e.g., starch, magnesium stearate, mannitol, sodium saccharin, talcum,cellulose, glucose, sucrose, lactose, trehalose, magnesium carbonate,and the like; solvents; dispersion media; coatings; antibacterial andantifungal agents; isotonic and absorption delaying agents; or any otherinactive ingredient. Selection of a pharmacologically acceptable carriercan depend on the mode of administration. Except insofar as anypharmacologically acceptable carrier is incompatible with the activecompound, its use in pharmaceutically acceptable compositions iscontemplated. Non-limiting examples of specific uses of suchpharmaceutical carriers can be found in Pharmaceutical Dosage Forms andDrug Delivery Systems (Howard C. Ansel et al., eds., Lippincott Williams& Wilkins Publishers, 7^(th) ed. 1999); Remington: The Science andPractice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams &Wilkins, 20^(th) ed. 2000); Goodman & Gilman's The Pharmacological Basisof Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional,10^(th) ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al., APhA Publications, 4^(th) edition 2003). These protocolsare routine and any modifications are well within the scope of oneskilled in the art and from the teaching herein.

A pharmaceutical composition disclosed herein can optionally include,without limitation, other pharmaceutically acceptable components (orpharmaceutical components), including, without limitation, buffers,preservatives, tonicity adjusters, salts, antioxidants, osmolalityadjusting agents, physiological substances, pharmacological substances,bulking agents, emulsifying agents, wetting agents, sweetening orflavoring agents, and the like. Various buffers and means for adjustingpH can be used to prepare a pharmaceutical composition disclosed herein,provided that the resulting preparation is pharmaceutically acceptable.Such buffers include, without limitation, acetate buffers, boratebuffers, citrate buffers, phosphate buffers, neutral buffered saline,and phosphate buffered saline. It is understood that acids or bases canbe used to adjust the pH of a composition as needed. Pharmaceuticallyacceptable antioxidants include, without limitation, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole, and butylated hydroxytoluene. Useful preservativesinclude, without limitation, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilizedoxy chloro composition, such as, e.g., sodium chlorite and chelants,such as, e.g., DTPA or DTPA-bisamide, calcium DTPA, andCaNaDTPA-bisamide. Tonicity adjustors useful in a pharmaceuticalcomposition include, without limitation, salts such as, e.g., sodiumchloride, potassium chloride, mannitol or glycerin and otherpharmaceutically acceptable tonicity adjustor. The pharmaceuticalcomposition may be provided as a salt and can be formed with many acids,including but not limited to, hydrochloric, sulfuric, acetic, lactic,tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueousor other protonic solvents than are the corresponding free base forms.It is understood that these and other substances known in the art ofpharmacology can be included in a pharmaceutical composition useful inthe invention.

A compound disclosed herein, or a composition comprising such acompound, may also be incorporated into a drug delivery platform inorder to achieve a controlled compound release profile over time. Such adrug delivery platform comprises a compound disclosed herein dispersedwithin a polymer matrix, typically a biodegradable, bioerodible, and/orbioresorbable polymer matrix. As used herein, the term “polymer” refersto synthetic homo- or copolymers, naturally occurring homo- orcopolymers, as well as synthetic modifications or derivatives thereofhaving a linear, branched or star structure. Copolymers can be arrangedin any form, such as, e.g., random, block, segmented, tapered blocks,graft, or triblock. Polymers are generally condensation polymers.Polymers can be further modified to enhance their mechanical ordegradation properties by introducing cross-linking agents or changingthe hydrophobicity of the side residues. If crosslinked, polymers areusually less than 5% crosslinked, usually less than 1% crosslinked.

Suitable polymers include, without limitation, alginates, aliphaticpolyesters, polyalkylene oxalates, polyamides, polyamidoesters,polyanhydrides, polycarbonates, polyesters, polyethylene glycol,polyhydroxyaliphatic carboxylic acids, polyorthoesters, polyoxaesters,polypeptides, polyphosphazenes, polysaccharides, and polyurethanes. Thepolymer usually comprises at least about 10% (w/w), at least about 20%(w/w), at least about 30% (w/w), at least about 40% (w/w), at leastabout 50% (w/w), at least about 60% (w/w), at least about 70% (w/w), atleast about 80% (w/w), or at least about 90% (w/w) of the drug deliveryplatform. Examples of biodegradable, bioerodible, and/or bioresorbablepolymers and methods useful to make a drug delivery platform aredescribed in, e.g., U.S. Pat. No. 4,756,911; U.S. Pat. No. 5,378,475;U.S. Pat. No. 7,048,946; U.S. Patent Publication 2005/0181017; U.S.Patent Publication 2005/0244464; U.S. Patent Publication 2011/0008437;each of which is incorporated by reference in its entirety.

In aspects of this embodiment, a polymer composing the matrix is apolypeptide such as, e.g., silk fibroin, keratin, or collagen. In otheraspects of this embodiment, a polymer composing the matrix is apolysaccharide such as, e.g., cellulose, agarose, elastin, chitosan,chitin, or a glycosaminoglycan like chondroitin sulfate, dermatansulfate, keratan sulfate, or hyaluronic acid. In yet other aspects ofthis embodiment, a polymer composing the matrix is a polyester such as,e.g., D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid,caprolactone, and combinations thereof.

One of ordinary skill in the art appreciates that the selection of asuitable polymer for forming a suitable disclosed drug delivery platformdepends on several factors. The more relevant factors in the selectionof the appropriate polymer(s), include, without limitation,compatibility of polymer with drug, desired release kinetics of drug,desired biodegradation kinetics of platform at implantation site,desired bioerodible kinetics of platform at implantation site, desiredbioresorbable kinetics of platform at implantation site, in vivomechanical performance of platform, processing temperatures,biocompatibility of platform, and patient tolerance. Other relevantfactors that, to some extent, dictate the in vitro and in vivo behaviorof the polymer include the chemical composition, spatial distribution ofthe constituents, the molecular weight of the polymer and the degree ofcrystallinity.

A drug delivery platform includes both a sustained release drug deliveryplatform and an extended release drug delivery platform. As used herein,the term “sustained release” refers to the release of a compounddisclosed herein over a period of about seven days or more. As usedherein, the term “extended release” refers to the release of a compounddisclosed herein over a period of time of less than about seven days.

In aspects of this embodiment, a sustained release drug deliveryplatform releases a compound disclosed herein with substantially firstorder release kinetics over a period of, e.g., about 7 days afteradministration, about 15 days after administration, about 30 days afteradministration, about 45 days after administration, about 60 days afteradministration, about 75 days after administration, or about 90 daysafter administration. In other aspects of this embodiment, a sustainedrelease drug delivery platform releases a compound disclosed herein withsubstantially first order release kinetics over a period of, e.g., atleast 7 days after administration, at least 15 days afteradministration, at least 30 days after administration, at least 45 daysafter administration, at least 60 days after administration, at least 75days after administration, or at least 90 days after administration.

In aspects of this embodiment, a drug delivery platform releases acompound disclosed herein with substantially first order releasekinetics over a period of, e.g., about 1 day after administration, about2 days after administration, about 3 days after administration, about 4days after administration, about 5 days after administration, or about 6days after administration. In other aspects of this embodiment, a drugdelivery platform releases a compound disclosed herein withsubstantially first order release kinetics over a period of, e.g., atmost 1 day after administration, at most 2 days after administration, atmost 3 days after administration, at most 4 days after administration,at most 5 days after administration, or at most 6 days afteradministration.

Aspects of the present disclosure provide, in part, ademyelination-related disorder. A demyelination-related disorder is anydisease or disorder of the nervous system in which the myelin sheath ofneurons is damaged. This damage impairs the conduction of signals in theaffected nerves. In turn, the reduction in conduction ability causesdeficiency in sensation, movement, cognition, or other functionsdepending on which nerves are involved. Both the central nervous systemand the peripheral nervous system can be involved.

Some demyelination-related disorders are caused by genetics, some byinfectious agents or toxins, some by autoimmune reactions, some byradiation injury, and some by unknown factors. Neuroleptics can alsocause demyelination. The precise mechanism of demyelination is notclearly understood but there is substantial evidence that the body's ownimmune system is at least partially responsible, causingdemyelination-related disorders to be considered autoimmune disorders.

Autoimmune disorders, including some demyelination disorders, arise froman overactive immune response of the body against substances and tissuesnormally present in the body resulting in a break in tolerance towardself-antigens. In other words, the body actually attacks its own cellsbecause the immune system mistakes some part of the body as a pathogenand attacks it. Characterized by the development of pathogenic T cellpopulations infiltrating the target organ or tissue, autoimmunedisorders may be restricted to certain organs or involve a particulartissue in different places.

Demyelination-related disorders can be broadly divided into central andperipheral nervous system disorders, depending on the organs mostaffected by the demyelination. Central nervous systemdemyelination-related disorders include, without limitation, multiplesclerosis, diffuse white matter injury in pre-term infants,neuromyelitis optica, acute disseminated encephalomyelitis, Marburgmultiple sclerosis, diffuse myelinoclastic sclerosis (Schilder'sdisease), Balo concentric sclerosis, solitary sclerosis, optic neuritis,transverse myelitis, amyotrophic lateral sclerosis, leukodystrophy(multiple variants, e.g. adrenoleukodystrophy, adrenomyeloneuropathy),Parkinson's disease, Alzheimer's disease, progressive supranuclearpalsy, stroke, traumatic brain injury, radiation inducedneuroinflammation, radiation somnolence syndrome, Devic's disease,inflammatory demyelinating diseases, CNS neuropathies like thoseproduced by vitamin B12 deficiency, central pontine myelinolysis,myelopathies like Tabes dorsalis (syphilitic myelopathy),leukoencephalopathies like progressive multifocal leukoencephalopathy,radiation induced central nervous system inflammation andleukodystrophies. Peripheral nervous system demyelination-relateddisorders include, without limitation, Guillain-Barré Syndrome, acuteinflammatory demyelinating polyneuropathy, chronic inflammatorydemyelinating polyneuropathy, demyelinating diabetic neuropathy,progressive inflammatory neuropathy, drug- or toxin-induced neuropathy,such as chemotherapy-induced neuropathy or radiation-induced neuropathyor organophosphate-induced neuropathy, anti-MAG peripheral neuropathy,Charcot-Marie-Tooth Disease, radiation induced neuropathy, and copperdeficiency.

In one embodiment, the demyelination-related disorder is multiplesclerosis (MS). Multiple sclerosis is currently treated by severalimmunomodulatory drugs that provide clinical benefit by modulatingpatient immune responses and producing anti-inflammatory effects. Thesedrugs delay disease progression but do not reverse disease pathology orrestore neurological function by restoring myelination of damagedneurons. The RXR agonist IRX4204 (194204, Formula XXIX) has an uniquemechanism of action in that it is a specific activator of RXR homodimersand RXR/Nurr1 heterodimers and simultaneously provides immunomodulatoryactivities and promotes remyelination. IRX4204 promotes thedifferentiation of suppressive Treg cells while simultaneouslyinhibiting the differentiation of pro-inflammatory Th17 cells, therebyfavorably affecting the aberrantly skewed Th17/Treg cell ratio whichunderlies human autoimmune diseases such as MS. Thus, by virtue of itseffects on Th17/Treg cell ratios, IRX4204 is expected to have clinicalbenefits similar to, or better than, current standard of care treatmentsin MS. IRX4204 additionally promotes remyelination of demyelinated CNSneurons. Accordingly, IRX4204 will not only delay disease progression inMS but also effect neural repair by regenerating healthy axons andneurons.

Aspects of the present disclosure includes, in part, reducing at leastone symptom associated with a demyelination-related disorder. The actualsymptoms associated with a demyelination-related disorder disclosedherein are well known and can be determined by a person of ordinaryskill in the art by taking into account factors, including, withoutlimitation, the location of the demyelination-related disorder, thecause of the demyelination-related disorder, the severity of thedemyelination-related disorder, the tissue or organ affected by thedemyelination-related disorder, and the demyelination-related disorderassociated with the inflammation. Non-limiting examples of symptomsreduced by a method of treating a demyelination-related disorderdisclosed herein include inflammation, fatigue, dizziness, malaise,elevated fever and high body temperature, extreme sensitivity to cold inthe hands and feet, weakness and stiffness in muscles and joints, weightchanges, digestive or gastrointestinal problems, low or high bloodpressure, irritability, anxiety, depression, blurred or double vision,ataxia, clonus, dysarthria, clumsiness, hand paralysis, hemiparesis,genital anaesthesia, incoordination, paresthesias, ocular paralysis,impaired muscle coordination, weakness (muscle), loss of sensation,impaired vision, neurological symptoms, unsteady gait, spasticparaparesis, incontinence, hearing problems, and speech problems.

Aspects of the methods of the present disclosure include, in part,treatment of a mammal. A mammal includes a human, and a human can be apatient. Other aspects of the present disclosure provide, in part, anindividual. An individual includes a mammal and a human, and a human canbe a patient.

Aspects of the present disclosure include, in part, administering acompound or a composition disclosed herein. As used herein, the term“administering” means any delivery mechanism that provides a compound ora composition disclosed herein to an individual that potentially resultsin a clinically, therapeutically, or experimentally beneficial result.

Administration of a compound or a composition disclosed herein include avariety of enteral or parenteral approaches including, withoutlimitation, oral administration in any acceptable form, such as, e.g.,tablet, liquid, capsule, powder, or the like; topical administration inany acceptable form, such as, e.g., drops, spray, creams, gels orointments; buccal, nasal, and/or inhalation administration in anyacceptable form; rectal administration in any acceptable form; vaginaladministration in any acceptable form; intravascular administration inany acceptable form, such as, e.g., intravenous bolus injection,intravenous infusion, intra-arterial bolus injection, intra-arterialinfusion and catheter instillation into the vasculature; perk andintra-tissue administration in any acceptable form, such as, e.g.,intraperitoneal injection, intramuscular injection, subcutaneousinjection, subcutaneous infusion, intraocular injection, retinalinjection, or sub-retinal injection or epidural injection;intravesicular administration in any acceptable form, such as, e.g.,catheter instillation; and by placement device, such as, e.g., animplant, a stent, a patch, a pellet, a catheter, an osmotic pump, asuppository, a bioerodible delivery system, a non-bioerodible deliverysystem or another implanted extended or slow release system. Anexemplary list of biodegradable polymers and methods of use aredescribed in, e.g., Handbook of Biodegradable Polymers (Abraham J. Dombet al., eds., Overseas Publishers Association, 1997).

A compound or a composition disclosed herein can be administered to amammal using a variety of routes. Routes of administration suitable fortreating a demyelination-related disorder as disclosed herein includeboth local and systemic administration. Local administration results insignificantly more delivery of a composition to a specific location ascompared to the entire body of the mammal, whereas, systemicadministration results in delivery of a composition to essentially theentire body of the individual. Routes of administration suitable for ortreating a demyelination-related disorder as disclosed herein alsoinclude both central and peripheral administration. Centraladministration results in delivery of a compound or a composition toessentially the central nervous system of the individual and includes,e.g., nasal administration, intrathecal administration, epiduraladministration as well as a cranial injection or implant. Peripheraladministration results in delivery of a compound or a composition toessentially any area of an individual outside of the central nervoussystem and encompasses any route of administration other than directadministration to the spine or brain. The actual route of administrationof a compound or a composition disclosed herein used can be determinedby a person of ordinary skill in the art by taking into account factors,including, without limitation, the type of demyelination-relateddisorder, the location of the demyelination-related disorder, the causeof the demyelination-related disorder, the severity of thedemyelination-related disorder, the duration of treatment desired, thedegree of relief desired, the duration of relief desired, the particularcompound or composition used, the rate of excretion of the compound orcomposition used, the pharmacodynamics of the compound or compositionused, the nature of the other compounds to be included in thecomposition, the particular route of administration, the particularcharacteristics, history and risk factors of the individual, such as,e.g., age, weight, general health and the like, the response of theindividual to the treatment, or any combination thereof. An effectivedosage amount of a compound or a composition disclosed herein can thusreadily be determined by the person of ordinary skill in the artconsidering all criteria and utilizing his best judgment on theindividual's behalf.

In an embodiment, a compound or a composition disclosed herein isadministered systemically to a mammal. In another embodiment, a compoundor a composition disclosed herein is administered locally to a mammal.In an aspect of this embodiment, a compound or a composition disclosedherein is administered to a site of a demyelination-related disorder ofa mammal. In another aspect of this embodiment, a compound or acomposition disclosed herein is administered to the area of ademyelination-related disorder of a mammal.

In another embodiment, the compound or composition is administereddirectly to the central nervous system by intrathecal administration,epidural administration, cranial injection or implant, or nasaladministration.

Aspects of the present specification provide, in part, administering atherapeutically effective amount of a compound or a compositiondisclosed herein. As used herein, the term “therapeutically effectiveamount” is synonymous with “therapeutically effective dose” and whenused in reference to treating a demyelination-related disorder means theminimum dose of a compound or composition disclosed herein necessary toachieve the desired therapeutic effect and includes a dose sufficient toreduce at least one symptom associated with a demyelination-relateddisorder. In aspects of this embodiment, a therapeutically effectiveamount of a compound or a composition disclosed herein reduces at leastone symptom associated with a demyelination-related disorder by, e.g.,at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, atleast 60%, at least 70%, at least 80%, at least 90% or at least 100%. Inother aspects of this embodiment, a therapeutically effective amount ofa compound or a composition disclosed herein reduces at least onesymptom associated with a demyelination-related disorder by, e.g., atmost 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most60%, at most 70%, at most 80%, at most 90% or at most 100%. In yet otheraspects of this embodiment, a therapeutically effective amount of acompound or a composition disclosed herein reduces at least one symptomassociated with a demyelination-related disorder by, e.g., about 10% toabout 100%, about 10% to about 90%, about 10% to about 80%, about 10% toabout 70%, about 10% to about 60%, about 10% to about 50%, about 10% toabout 40%, about 20% to about 100%, about 20% to about 90%, about 20% toabout 80%, about 20% to about 20%, about 20% to about 60%, about 20% toabout 50%, about 20% to about 40%, about 30% to about 100%, about 30% toabout 90%, about 30% to about 80%, about 30% to about 70%, about 30% toabout 60%, or about 30% to about 50%. In still other aspects of thisembodiment, a therapeutically effective amount of a compound or acomposition disclosed herein is the dosage sufficient to reduces atleast one symptom associated with a demyelination-related disorder for,e.g., at least one week, at least one month, at least two months, atleast three months, at least four months, at least five months, at leastsix months, at least seven months, at least eight months, at least ninemonths, at least ten months, at least eleven months, or at least twelvemonths.

The amount of active component in a compound or a composition disclosedherein for treating a demyelination-related disorder can be varied sothat a suitable dosage is obtained. The actual therapeutically effectiveamount of a compound or a composition disclosed herein to beadministered to a mammal can be determined by a person of ordinary skillin the art by taking into account factors, including, withoutlimitation, the type of the demyelination-related disorder, the locationof the demyelination-related disorder, the cause of thedemyelination-related disorder, the severity of thedemyelination-related disorder, the duration of treatment desired, thedegree of relief desired, the duration of relief desired, the particularcompound or composition used, the rate of excretion of the compound orcomposition used, the pharmacodynamics of the compound or compositionused, the nature of the other compounds to be included in thecomposition, the particular route of administration, the particularcharacteristics, history and risk factors of the individual, such as,e.g., age, weight, general health and the like, the response of theindividual to the treatment, or any combination thereof. An effectivedosage amount of a compound or a composition disclosed herein can thusreadily be determined by the person of ordinary skill in the artconsidering all criteria and utilizing his best judgment on theindividual's behalf.

Additionally, where repeated administration of a compound or acomposition disclosed herein is used, the actual effect amount of acompound or a composition disclosed herein will further depend uponfactors, including, without limitation, the frequency of administration,the half-life of the compound or composition disclosed herein, or anycombination thereof. In is known by a person of ordinary skill in theart that an effective amount of a compound or a composition disclosedherein can be extrapolated from in vitro assays and in vivoadministration studies using animal models prior to administration tohumans. Wide variations in the necessary effective amount are to beexpected in view of the differing efficiencies of the various routes ofadministration. For instance, oral administration generally would beexpected to require higher dosage levels than administration byintravenous or intravitreal injection. Variations in these dosage levelscan be adjusted using standard empirical routines of optimization, whichare well-known to a person of ordinary skill in the art. The precisetherapeutically effective dosage levels and patterns are preferablydetermined by the attending physician in consideration of theabove-identified factors.

As a non-limiting example, when administering a compound or acomposition disclosed herein to a mammal, a therapeutically effectiveamount generally is in the range of about 0.001 mg/kg/day to about 100.0mg/kg/day. In aspects of this embodiment, an effective amount of acompound or a composition disclosed herein can be, e.g., about 0.01mg/kg/day to about 0.1 mg/kg/day, about 0.03 mg/kg/day to about 3.0mg/kg/day, about 0.1 mg/kg/day to about 3.0 mg/kg/day, or about 0.3mg/kg/day to about 3.0 mg/kg/day. In yet other aspects of thisembodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at least 0.001 mg/kg/day, atleast 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, atleast 10 mg/kg/day, or at least 100 mg/kg/day. In yet other aspects ofthis embodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at most 0.001 mg/kg/day, atmost 0.01 mg/kg/day, at most 0.1 mg/kg/day, at most 1.0 mg/kg/day, atmost 10 mg/kg/day, or at most 100 mg/kg/day.

As another non-limiting example, when administering a compound or acomposition disclosed herein to a mammal, a therapeutically effectiveamount generally is in the range of about 0.001 mg/m²/day to about 100.0mg/m²/day. In aspects of this embodiment, an effective amount of acompound or a composition disclosed herein can be, e.g., about 0.01mg/m²/day to about 0.1 mg/m²/day, about 0.03 mg/m²/day to about 3.0mg/m²/day, about 0.1 mg/m²/day to about 3.0 mg/m²/day, or about 0.3mg/m²/day to about 3.0 mg/m²/day. In yet other aspects of thisembodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at least 0.001 mg/m²/day, atleast 0.01 mg/m²/day, at least 0.1 mg/m²/day, at least 1.0 mg/m²/day, atleast 10 mg/m²/day, or at least 100 mg/m²/day. In yet other aspects ofthis embodiment, a therapeutically effective amount of a compound or acomposition disclosed herein can be, e.g., at most 0.001 mg/m²/day, atmost 0.01 mg/m²/day, at most 0.1 mg/m²/day, at most 1.0 mg/m²/day, atmost 10 mg/m²/day, or at most 100 mg/m²/day.

Dosing can be single dosage or cumulative (serial dosing), and can bereadily determined by one skilled in the art. For instance, treatment ofa demyelination-related disorder may comprise a one-time administrationof an effective dose of a compound or a composition disclosed herein. Asa non-limiting example, an effective dose of a compound or a compositiondisclosed herein can be administered once to a mammal, e.g., as a singleinjection or deposition at or near the site exhibiting a symptom of ademyelination-related disorder or a single oral administration of thecompound or a composition. Alternatively, treatment of ademyelination-related disorder may comprise multiple administrations ofan effective dose of a compound or a composition disclosed hereincarried out over a range of time periods, such as, e.g., daily, onceevery few days, weekly, monthly or yearly. As a non-limiting example, acompound or a composition disclosed herein can be administered once ortwice weekly to a mammal. The timing of administration can vary frommammal to mammal, depending upon such factors as the severity of amammal's symptoms. For example, an effective dose of a compound or acomposition disclosed herein can be administered to a mammal once amonth for an indefinite period of time, or until the mammal no longerrequires therapy. A person of ordinary skill in the art will recognizethat the condition of the mammal can be monitored throughout the courseof treatment and that the effective amount of a compound or acomposition disclosed herein that is administered can be adjustedaccordingly.

A compound or a composition disclosed herein as disclosed herein canalso be administered to a mammal in combination with other therapeuticcompounds to increase the overall therapeutic effect of the treatment.The use of multiple compounds to treat an indication can increase thebeneficial effects while reducing the presence of side effects.

Aspects of the present specification may also be described as follows:

EXAMPLES

The following non-limiting examples are provided for illustrativepurposes only in order to facilitate a more complete understanding ofrepresentative embodiments now contemplated. These examples should notbe construed to limit any of the embodiments described in the presentspecification, including those pertaining to the methods of treating anautoimmune disorder, in particular a demyelination-related disorderusing the RXR agonists disclosed herein, uses of a RXR agonistsdisclosed herein to manufacture a medicament and/or treat an autoimmunedisorder, in particular a demyelination-related disorder, methods ofpromoting Treg cell differentiation in an individual, inhibiting Th17cell differentiation, or both, as well as uses of a RXR agonistsdisclosed herein to promote Treg cell differentiation in an individual,inhibit Th17 cell differentiation, or both.

Example 1 RXR Agonists Induce Treg Cell Differentiation

To determine whether a RXR agonist can induce Treg cell differentiation,the ability of an RXR agonist to promote Treg cell differentiation underTreg cell differentiation conditions was assessed by monitoring Foxp3and α4β7 expression. Naïve CD4⁺ CD25⁻ FoxP3⁻ cells were purified from aFoxp3-GFP mouse using flow cytometry by sorting and isolating based upona GFP⁻ phenotype. These cells were then cultured under Treg celldifferentiation conditions by treating the cells with αCD3 and αCD28polyclonal antibodies in the presence of IL-2 and TGF-β. The culturedcells were incubated with RXR agonist 194204 (Formula XXIX, IRX4204) at0.1 nM, 1.0 nM and 10 nM and the expression of Foxp3 and α4β7 wasanalyzed. The results indicate that RXR agonist exerted significantimpact on the expression of Foxp3, inducing nearly 100% Foxp3⁺ T cellsat concentrations of 1 nM or higher. FIG. 1A. These results alsoindicate that RXR agonist 194204 also induced expression of α4β7 (a guthoming receptor). FIG. 1B. These results indicate that RXR agonistscould be useful in reducing a symptom of an autoimmune disorder or atransplant rejection.

Example 2 RXR Agonists Regulate T Cell Differentiation

To determine whether a RXR agonist can regulate T cell differentiation,the ability of an RXR agonist to promote Treg cell differentiation andinhibit Th17 cell differentiation under Th17 cell differentiationconditions was assessed by monitoring Foxp3 and IL-17A expression. NaiveCD4⁺ CD25⁻ FoxP3⁻ cells were purified from a Foxp3-GFP mouse using flowcytometry by sorting and isolating based upon a GFP⁻ phenotype. Thesecells were then cultured under Th17 cell differentiation conditions inmedia with 0 nM, 1 nM, 10 nM, and 100 nM of RXR agonist 194204 (FormulaXXIX, IRX4204) and the expression of Foxp3 and IL-17A was analyzed. See,e.g., Elias, et al., Blood 111(3):1-13-1020 (2008). The resultsindicated that as the concentration of the RXR agonist increased, Foxp3expression increased, indicating an increased presence of Treg cells(FIG. 2A). Additionally, the data demonstrate that as the concentrationof the RXR agonist increased, IL-17A expression decreased, indicating adecreased presence of Th17 cells (FIG. 2B). These results indicate thatRXR agonists regulate T cell differentiation by promotingdifferentiation of immunosuppressive Treg cells and concurrentlyinhibiting differentiation of inflammatory Th17 cells from naïve T cellsin vitro.

Example 3 RXR Agonists Regulate T Cell Differentiation Independent ofRAR Signaling

To determine whether a RXR agonist can mediate its effects via RAR/RXRreceptor heterodimers, via RXR receptor homodimers, or via some otherRXR containing complex, T cells were incubated with a RXR agonist in thepresence of a pan-RAR antagonist and the expression of Foxp3 wasassessed. Naïve CD4⁺ CD25⁻ FoxP3⁻ cells were purified from a Foxp3-GFPmouse using flow cytometry by sorting and isolating based upon a GFP⁻phenotype. These cells were then cultured under Treg celldifferentiation conditions by treating the cells with αCD3 and αCD28polyclonal antibodies in the presence of IL-2 and TGF-β. The culturedcells were incubated with RXR agonist 194204 at 1.0 nM together with 0nM, 1 nM, or 10 nM of a pan-RAR antagonist 194310. The cultured cellswere then assayed for the expression of Foxp3. The results indicate thatthe inclusion of a pan-RAR antagonist only partially blocked theinduction of Foxp3 expression observed with an RXR agonist alone. FIG.3. However, this partial inhibition of Fox3p expression may actually bedue to the blocking of the effects of endogenous retinoic acid in theculture medium. As such, these results indicate that the observedconversion of T cells into Treg cells appears to occur through the useof RXR receptor homodimers and/or some other RXR containing complex, andnot through a RAR-mediated mechanism.

Example 4 T Cell Differentiation is Mediated Through RXR Signaling byRXR Agonists

To determine whether a RXR agonist can mediate its effects via an RXRαreceptor homodimers, RXRβ receptor homodimers, RXRγ receptor homodimers,or any combination thereof, or the corresponding RAR/RXR heterodimers,receptor-mediated transactivation assays were performed. Fortransactivation assays assessing RXR homodimer signaling, CV-1 cellswere transfected with 1) an expression construct including a full lengthRXRα, RXRβ, or RXRγ; and 2) a rCRBPII/RXRE-tk-Luc reporter constructthat included RXR homodimer-specific RXRE/DR1 responsive element linkedto a luciferase gene. For transactivation assays assessing RAR/RXRheterodimer signaling, CV-1 cells were transfected with 1) an expressionconstruct comprising a fusion protein including an estrogen receptor(ER) DNA binding domain linked to the ligand binding domain of RARα,RARβ, or RARγ and 2) a ERE-tk-Luc reporter construct that included anestrogen receptor responsive element linked to a luciferase gene. TheER-RAR fusion proteins provided an accurate readout of only thetransfected ER-RAR. After transfection, CV-1 cells were treated with RXRagonist 194204 at increasing concentrations for 20 hours beforemeasuring luciferase activity. Luciferase activity is expressed aspercent of maximal activity obtained using 1 μM RXR agonist 194204 forRXRs and 1 μM all-trans-retinoic acid (ATRA) for RARs (Table 1). Dataare mean values±SE from five independent experiments.

TABLE 1 RXR Agonist Potencies in Activating RXRs and RARs EC₅₀ (nM) EC₅₀(nM) Efficacy (% of 1 μM 194204) Efficacy (% of 1 μM ATRA) CompoundStructure RXRα RXRβ RXRγ RARα RARβ RARγ 194204 (IRX4204)

0.08 ± 0.01 100 0.47 ± 0.05 100 0.09 ± 0.01 100 >1,000 >1,000 >1,000

These results indicate that RXR agonist 194204 activated RXR receptorswith very high potency (EC₅₀<0.5 nM) for all three RXR subtypes (Table1). In contrast, EC₅₀ of the RXR agonist for RARs was >1,000 nM withminimal activity detected at ≧1 μM. This differencerepresents >2,000-fold selectivity for RXRs over RARs in functionaltransactivation assays. Additionally, these data demonstrate that RXRagonist 194204 was more than 1,000-fold more potent in activating RXRreceptors rather than RAR receptors. These results indicate that Tregdifferentiation was mediated through a RXR signaling pathway and not viaa RAR signaling pathway. Also, using appropriate receptor and reporterconstructs, RXR agonist 194204 was shown not to transactivate so called“permissive RXR heterodimers” PPAR/RXR, FXR/RXR and LXR/RXR (FIG. 8A-C).In this regard, RXR agonist 194204 is distinct from other RXR agonists.Additionally, 194204 selectively activates the Nurr1/RXR permissiveheterodimer (FIG. 8D). Thus, RXR agonist 194204 has a unique profile inthat it selectively activates only RXR homodimers and Nurr1/RXRheterodimers.

Example 5 Binding Affinity of RXR Agonists

To determine the binding affinity for a RXR agonist, competitivedisplacement assays were performed. RXRα, RXRβ, RXRγ, RARα, RARβ, orRARγ were expressed in SF21 cells using a baculovirus expression systemand the resulting proteins were purified. To determine the bindingaffinity for a RXR agonist for an RXR, purified RXRα, RXRβ, and RXRγwere separately incubated with 10 nM [³H]-9CRA, and the binding affinityof the RXR agonist 194204 was determined by competitive displacement of[³H]-9CRA from the receptor. To determine the binding affinity for a RXRagonist for an RAR, purified RARα, RARβ, and RARγ were incubated with 5nM [³H]-ATRA, and the binding affinity of the RXR agonist 194204 wasdetermined by competitive displacement of [³H]-ATRA from the receptor.Ki values are mean values of at least two independent experiments (Table2). Standard errors (±) among independent experiments are indicated.

As shown in Table 2, RXR agonist 194204 displayed high affinity forRXRα, RXRβ, and RXRγ with Ki values being 1.7, 16, and 43 nM,respectively. In contrast, the RXR agonist 194204 bound with very lowaffinity to each of the RARs (Ki values being >1,000 nM). These dataindicate that 194204 is highly selective for the RXRs relative to theRARs.

TABLE 2 RXR Agonist Binding Affinities RXR Binding Affinity RAR BindingAffinity Ki (nM) Ki (nM) Compound Structure RXRα RXRβ RXRγ RARα RARβRARγ 194204

1.7 ± 0.1 16 ± 1.0 43 ± 3.0 6344 ± 674 7552 ± 638 4742 ± 405

Example 6 RXR Agonists Attenuate EAE in B6 Mice

To determine whether a RXR agonist can attenuate multiple sclerosis,C57BL/6 (B6) mice were immunized (day 0) to induce experimentalautoimmune encephalomyelitis (EAE) by subcutaneous (s.c.) injection atthe base of their spine with 200 μL of adjuvant containing 125 μg myelinoligodendrocyte glycoprotein peptide (35-55) (MOG peptide; PeptidesInternational, Louisville, Ky.) and 400 μg non-viable M. tuberculosisH37 desiccate emulsified in a mixture of incomplete Freund's adjuvantand phosphate buffered saline (PBS). Mice were also given 200 ng ofpertussis toxin in PBS administered by inter-peritoneal (i.p.) injectionon the same day as MOG emulsion injection (day 0) and 2 days later (day2). Starting on day 7 after immunization, mice were given the RXRagonist IRX4204 (50 μg) or vehicle control i.p. every other day for theduration of the experiment (n=6-7 mice/group). Statistics show theresults of a Mann Whitney test (analyzed from start of treatment to theend of the experiment). Mice were scored using the following scale:0—Mice have no disease, 1—Mice have distal limp tail or rear legweakness (paresis), 1.5—Mice have distal limp tail and rear legweakness, 2—Mice have complete limp tail and rear leg weakness, 2.5—Micehave complete limp tail and weakness in both rear legs, 3—Mice havecomplete limp tail and paralysis in both rear legs, 3.5—Mice havecomplete limp tail, paralysis in both rear legs, and forelimb weakness.Mice receiving a score of 3.5 were immediately euthanized.

FIG. 5 depicts scores of disease severity over time. The resultsindicate that administration of a RXR agonist (194204, IRX4204) at 50 μgsignificantly reduces the symptoms of EAE in mice. Efficacy of the RXRagonist was observed after the first administration (day 7) andmaintained throughout the course of the study (day 20).

A dose titration experiment was also conducted in EAE mice. EAE wasinduced in 28 B6 mice with MOG/CFA and PT as above. Mice were scored onday 7 as indicated above and divided into groups by score so means areas equal as possible. Starting day 8, mice were scored and injected witha vehicle control or IRX4204 (50 μg, 100 μg, or 200 μg) every day.

The mice were weighed at the beginning of experiment and every day theyhad a score of 2.5 or higher and mice were euthanized if they lost 15%or more of their start weight. All mice were treated with IRX4204 hadsignificantly less disease overall (FIG. 10). At the completion of theexperiment, the vehicle control and 200 μg/day groups were euthanizedand spleen and CNS samples obtained.

The spleen samples were evaluated for CD49d (FIG. 11A) and CCR6 (FIG.11B), and IRX4204 treatment lowered CCR6, but not CD49d, expression onCD4 T cells. Additionally, CD4+ CD25hi cells (generally consisting ofTReg) were reduced, although the frequency was not altered (FIGS. 12Aand 12B). The total number of effector and memory CD4 T cells, asindicated by CD44 expression, decreased with IRX4204 treatment (FIG.12C) and the total number of recently activated CD4 T cells, asindicated by expression of both CD69 and CD44, was also decreased withIRX4204 treatment (FIG. 12D).

In the CNS, the total the total number of infiltrating CD4 T cells wasreduced with IRX4204 treatment (FIG. 13). Restimulation withPMA/Ionomycin was used to help detect the cytokine production. Both IFNγ(FIGS. 14A and 14B) and TNF (FIGS. 14C and 14D) were significantlyreduced with treatment. Co-expression of IFNg and IL-17A by CD4 T cellsin CNS was quantified, but was not significantly different betweengroups (FIG. 15A-15C).

Example 7 RXR Agonist-Treated Mice have Reduced Central Nervous SystemInfiltrating Cells

To determine whether a RXR agonist can reduce central nervous system(CNS) infiltrating cells, C57BL/6 (B6) mice were treated as described inExample 6. On day 20 after immunization, mice were sacrificed andperfused with phosphate buffered saline (PBS). Brain and spinal cordtissue was isolated, digested with DNase and LIBERASE DL® (RocheDiagnostics, Indianapolis, Ind.) for 30 minutes, and homogenized through70 micron nylon mesh filters. Resulting cells were placed over a Percollgradient to remove myelin. The remaining cells (microglia and CNSinfiltrating cells) were counted, stained for molecules of interest, andrun on a flow cytometer. Based on the frequencies obtained by FACS ofthese cell populations, total cell numbers of CNS infiltratingleukocytes expressing CD45, including CD4⁺ T cells and CD11c⁺ CD11b⁺myeloid dendritic cells (DC), were calculated.

FIG. 6 depicts the number of CD4⁺ cells (FIG. 6A) or CD11c⁺ CD11b⁺ cells(myeloid DC; FIG. 6B) in mice treated with the RXR agonist 194204 versesthe vehicle control. There was a significant reduction in theinfiltration of both CD4⁺ cells and CD11c⁺ CD11b⁺ cells in animalstreated with a RXR agonist as compared to the control. As disease ispropagated in the CNS through the CD4⁺ cells infiltrating the CNS andbecoming re-activated by CD11c⁺ CD11b⁺ cells, this suggests that part ofthe mechanism of action in this model is to limit the presence of thecells in the CNS.

Example 8 RXR Agonists Attenuate EAE in SJL Mice

To determine whether a RXR agonist can attenuate multiple sclerosis, SJLmice were immunized to induce EAE by s.c. injection at the base of theirspine with 200 μL of adjuvant containing 200 μg proteolipid proteins(139-151) (PLP peptide; Peptides International, Louisville, Ky.) and 400μg of non-viable M. tuberculosis H37 desiccate emulsified in a mixtureof incomplete Freund's adjuvant and PBS. Mice were also given 150 ng ofpertussis toxin in PBS i.p. on the same day as PLP emulsion injectionand 2 days later. Starting day 7 after immunization, mice were given theRXR agonist IRX4204 (50 μg) or vehicle control i.p. every other day forthe duration of the experiment (n=6 mice/group). Mice were scored usingthe scale described in Example 6.

The results indicate that administration of a RXR agonist (194204,IRX4204) significantly reduces the symptoms of EAE in mice. Table 3shows the features of a RXR agonist IRX4204 treatment in SLJ mice. FIG.7 depicts scores of disease severity over time. Efficacy of the RXRagonist was observed after the second administration (day 8) andmaintained throughout the course of the study (day 14).

TABLE 3 RXR agonist Treatment in SJL Mice Clinical Features VehicleIRX4204 Mean Maximum Score 3.2 ± 0.6 1.5 ± 1.4 Disease Incidence 6/6 4/6Death from Disease 4/6 0/6

Example 9 RXR Agonist IRX4204 as a Selective Activator of Nurr1/RXRPermissive Heterodimer

In order to determine which permissive RXR heterodimer is activated bythe RXR agonist IRX4204 (194204), receptor transactivation assays werecarried out as follows for PPARγ/RXR, FXR/RXR, LXRα/RXR, LXRβ/RXR, andNurr1/RXR. For PPARγ: CV-1 cells were transfected with3×(rAOX/DR1)-tk-Luc reporter gene and an expression vector for PPARγ.For FXR:CV-1 cells were transfected with 3×(IBABP/IRI)-tk-Luc reportergene and vectors for FXR and RXRα. For LXR:CV-1 cells were transfectedwith 3×(PLTP/LXRE)-tk-Luc reporter gene with vectors for LXRα or LXRβ.For Nurr1: COS7 cells were transfected with 3×NBRE-tk-luc reporter geneand full length Nurr-1 with or without full-length RXRα plasmid. Cellswere then treated with vehicle or IRX4204 for 20 hr. Luciferase datawere normalized to co-transfected β-gal activity. Luciferase activitywas expressed as percent of maximal activity obtained using specificagonists. Rosiglitazone (PPARγ), GW4064 (FXR), T0901317 (LXR). The dataindicate that IRX4204 does not activate FXR/RXR (FIG. 8A), LXRα/RXR orLXRβ/RXR (FIG. 8B), or PPARγ/RXR (FIG. 8C). In contrast, IRX4204potently (EC₅₀<1 nm) activates the Nurr1/RXR heterodimer. These datacollectively indicate that IRX4204 (194204) is a unique RXR agonist inthat it selectively activates the Nurr1/RXR heterodimer but not thePPARγ/RXR, FXR/RXR or LXR/RXR heterodimers.

Example 10 Effect of RXR Agonists on Oligodendrocyte Precursor CellDifferentiation

The goal of this study was to evaluate the effect of IRX4204 ondifferentiation of oligodendrocyte precursor cells (OPCs) intooligodendrocytes. OPCs were generated from a neurosphere culture ofE14.5 PLP-EGFP (on C57BL/6J background) mouse brains. The isolated OPCswere treated with IRX4204 to evaluate the expression of greenfluorescent protein (EGFP), which correlates with differentiation ofOPCs into oligodendrocytes. The EGFP expressing cells were quantifiedwith Cellomics Neuronal Profiling Algorithm. The positive (T3) controldemonstrated differentiation of OPCs as expected. The resultsdemonstrate that IRX4204 promotes OPC differentiation intooligodendrocytes as shown by the increase in the number of the EGFPpositive cells compared to negative control (DMSO). All testedconcentrations but the lowest concentration (1⁻⁶ μM) showed asignificant increase in OPC differentiation into oligodendrocytes (FIG.9, data for IRX4204 are shown as open bars with concentrations expressedin μM).

The EGFP expressing cells in controls and all compounds were quantifiedwith Cellomics Neuronal Profiling Algorithm. The experiment wassuccessful as demonstrated by the significant increase in % EGFP cellsin positive control (T3; 8.5%) compared to the negative control (DMSO;2.3%). IRX4204 promotes OPC differentiation into oligodendrocytes asdemonstrated by the dose dependent increase in the number of the EGFPpositive cells compared to negative control (DMSO). IRX4204 did not showany differences in total cell number and pyknotic cells compared tocontrols. The results from this study demonstrate that IRX4204 promotesOPC differentiation. The data show a dose-dependent increase in thepercentage of EGFP cells compared to the negative control. These dateindicate that IRX4204 promotes the growth of myelin-forming cells incell culture.

Example 11 IRX4204 Enhances Central Nervous System (CNS) Remyelinationin an In Vivo Model by Acting Directly on the Remyelination Process

A focal toxin (ethidium bromide) induced rat model of demyelination isused to ascertain the direct effects of IRX4204 on acute demyelinationindependent of the immunomudulatory effects of IRX4204. The experimentuses rats of relatively advanced age (1 year) since such rats undergoremyelination in a less efficient manner, thereby providing data thatare more relevant to the clinical treatment of human patients withmultiple sclerosis or other demyelination disorders.

Focal demyelination is induced in one year old rats (approximately 300 gin weight) by injecting stereotactically 5 μl of ethidium bromidesolution (0.01% vol/vol in saline) in a bilateral manner into the caudalcerebellar peduncles (CCP). Starting seven days after injection of theethidium bromide, the rats are treated by oral gavage with 10 mg/kg/dayof IRX4204 (in DMSO and corn oil) or vehicle (DMSO and corn oil) forfourteen days (day 7 to day 21 post-ethidium bromide treatment). Therats are killed on day 24 post-ethidium bromide treatment for analysisof remyelination by quantitative polymerase chain reaction (qPCR) andmicroscopy.

Analysis of the lesions revealed the following: the densities of Olig2⁺oligodendrocyte lineage cells and CC1+differentiated oligodendrocytesincreased in IRX4204-treated animals relative to vehicle treatedanimals; Nkx2.2+oligodendrocyte precursor cells (OPCs) increased inIRX4204-treated lesions relative to vehicle treated lesions. Also,real-time qPCR analysis of lesion samples show an increase in Mbpexpression and an increase in Pdgfra expression indicating higher levelsof myelin regeneration in IRX4204-treated animals. Ultrastructuralanalyses of CCP lesions further demonstrate that IRX4204 treatmentresults in more remyelinated axons in animals than vehicle treatment.AG-ratio analysis (this ratio is that of axon diameter to myelinatedaxon) also shows that IRX4204-treated animals have a lower G-ratio thanvehicle treated animals and that this lower ratio is due to theformation of thicker remyelinated sheaths surrounding axons inIRX4204-treated animals. All these findings are consistent with anincrease in CNS remyelination in IRX4204-treated animals.

Example 12 IRX4204 Accelerates Remyelination in a Mouse Model ofDemyelination

The cuprizone (bis-cyclohexanone oxaldihydrazone) model facilitatesreliable, reproducible and unequivocal analysis of myelin parameters inboth white and grey matter. The cuprizone model is a model for toxicdemyelination. In this model, young mice are fed with the copperchelator cuprizone, leading to oligodendrocyte death and a subsequentreversible demyelination. cuprizone-fed mice with rapamycin, a drug thatblocks mTOR and spontaneous remyelination, allowing betterquantification of oligodendrocyte turnover. In the acute cuprizoneparadigm, male C57BL/6 mice at 6 to 9 weeks of age are fed a diet ofchow mixed with 0.2% cuprizone over the course of 6 weeks. By the thirdweek of cuprizone feeding, consistent demyelination can be observed inthe corpus callosum, the largest white matter tract in the mouse brain.Demyelination reaches a maximum at 5 or 6 weeks. Chronic demyelinationcan be induced if C57BL/6 mice are maintained on a diet with cuprizonefor 12 weeks.

In this study, the acute (6-week) model will be used to assessremyelination potential of IRX4204. Mice are fed a cuprizone-containingdiet and injected with rapamycin daily for 6 weeks to inducedemyelination. One group of animals is sacrificed at 6 weeks to evaluatedemyelination. The remaining mice are continued on thecuprizone/rapamycin regimen, and treatment with IRX4204 or vehiclecontrol is initiated for a three week treatment period. At the end ofthe study, all mice are sacrificed and one or more of the followingparameters are determined: (1) PPD (p-phenylenediamine) staining tovisualize and quantify myelinated axons in corpus callosum to assessdemyelination and remyelination in white matter; (2) myelin proteolipidprotein (PLP) immunostaining to visualize and quantify myelin inhippocampus to assess demyelination and remyelination in grey matter(hippocampus); (3) PLP immunostaining to visualize and quantify myelinin cortex to assess demyelination and remyelination in grey matter(cortex); (4) PDGFRα immunostaining to visualize and quantify OPCs incorpus callosum; (5) GSTpi immunostaining to visualize and quantifyoligodendrocytes in corpus callosum; (6) Iba1 (ionized calcium-bindingadapter molecule 1) and/or Mac-2 (galectin-3) immunostaining tovisualize and quantify total and activated microglia in corpus callosum;(7) GFAP (glial fibrillary acidic protein) immunostaining to vivalizeand quantify astrocytes in corpus callosum To assess astroglialactivation; and (8) 3D-electron microscopy in corpus callosum to assessratio of myelinated and non-myelinated axons, internodal length,G-ratio, mitochondrial changes, etc.

Example 13 A Human Clinical Trial to Ascertain Effects of IRX4204Treatment on Myelin Repair in Multiple Sclerosis Patients withRelapsing-Remitting Disease

A proof of concept clinical trial of IRX4204 is conducted in multiplesclerosis (MS) patients to ascertain the direct effects of IRX4204 onmyelin repair in patients with relapsing-remitting MS. Patients withrelapsing-remitting MS are recruited to participate in the clinicaltrial and are provided informed consent describing risks and potentialbenefits of participation. The MS patients are treated with one ofseveral dose levels of IRX4204, ranging from 1 mg/day to 40 mg/day,administered orally as capsules, once per day. Some patients arerandomized to receive a placebo dose using matching capsules, which donot contain IRX4204. Patients are dosed for a minimum of 30 days, and aslong as 180 days. Patients are assessed for the status of myelin damageand speed of repair of demyelination in MS lesions that occur over thisperiod of time in their brains, spinal cords, and/or optic nerves.Quantitation of myelin damage and repair is performed at baseline andperiodically through the dosing, using specialized imaging methods,which specifically examine and quantitate myelin damage and repair inthese parts of the nervous system. Such methods include, but are notlimited to, Positron Emission Tomography (PET) scanning, utilizingimaging agents such as the thioflavine-T derivative2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (PIB), which also bindsto amyloid plaques. This compound is useful for useful for quantitatingmyelin repair. Alternatively, magnetic resonance imaging (MRI) usingspecial contrast agents that bind to or enhance the appearance of areasof myelin damage or repair is utilized; or special MRI analyticalalgorithms, such as magnetization transfer imaging, or diffusion tensorimaging, are utilized to quantitate myelin damage and repair in theIRX4204-treated patients compared to the placebo-treated patients. Doseresponse relationships of IRX4204 to myelin protection or repair areanalyzed across the cohorts of patients treated with various dose levelsof IRX4204. In addition to the quantitation of myelin damage and repairby imaging methods, the clinical status of the MS patients' diseaseprogression is preliminarily evaluated using standard clinical endpointsfor MS clinical trials, such as the Expanded Disability Status Scale(EDSS). The EDSS is a 10 point scale which quantitates the MS patients'levels of disability by evaluating physical activities of daily life,such as walking, swallowing, bowel and bladder function, etc. Inaddition, visual acuity testing is performed to quantitate effects ofIRX4204 on myelin damage and repair in the optic nerves.

Example 14 A Human Clinical Trial to Evaluate the Effects of IRX4204Treatment on Progression of Disability in Multiple Sclerosis Patientswith Relapsing-Remitting Disease

A clinical trial to provide definitive evidence of benefit of IRX4204treatment on progression of disability in MS is conducted in MS patientswith relapsing-remitting MS. Patients with relapsing-remitting MS arerecruited to participate in the clinical trial and are provided informedconsent describing risks and potential befits of participation. The MSpatients are randomized to treatment with a dose level of IRX4204, inthe range of 1 to 40 mg/day administered orally, or matching placebo,for 24 months. The primary clinical efficacy outcome measure is theEDSS, a 10 point scale which quantitates the MS patients' levels ofdisability by evaluating physical activities of daily life, such aswalking, swallowing, bowel and bladder function, etc. The clinical trialuses a sample size selected to demonstrate to a statisticallysignificant level, a difference in change in the mean EDSS over time, ofa least 1 point, between the IRX4204-treated group, and theplacebo-treated group, at the end of 24 months of treatment. Inaddition, in this clinical trial visual acuity testing is performed toquantitate effects of IRX4204 on myelin damage and repair in the opticnerves. A sample size is selected which will demonstrate to astatistically level, a difference in change in visual acuity over time,of a least 1 line on the standard visual acuity chart, between theIRX4204-treated group, and the placebo-treated group, at the end of 24months of treatment.

In closing, it is to be understood that although aspects of the presentspecification are highlighted by referring to specific embodiments, oneskilled in the art will readily appreciate that these disclosedembodiments are only illustrative of the principles of the subjectmatter disclosed herein. Therefore, it should be understood that thedisclosed subject matter is in no way limited to a particularmethodology, protocol, and/or reagent, etc., described herein. As such,various modifications or changes to or alternative configurations of thedisclosed subject matter can be made in accordance with the teachingsherein without departing from the spirit of the present specification.Lastly, the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention, which is defined solely by the claims.Accordingly, the present invention is not limited to that precisely asshown and described.

Certain embodiments of the present invention are described herein,including the best mode known to the inventors for carrying out theinvention. Of course, variations on these described embodiments willbecome apparent to those of ordinary skill in the art upon reading theforegoing description. The inventor expects skilled artisans to employsuch variations as appropriate, and the inventors intend for the presentinvention to be practiced otherwise than specifically described herein.Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above-describedembodiments in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

Groupings of alternative embodiments, elements, or steps of the presentinvention are not to be construed as limitations. Each group member maybe referred to and claimed individually or in any combination with othergroup members disclosed herein. It is anticipated that one or moremembers of a group may be included in, or deleted from, a group forreasons of convenience and/or patentability. When any such inclusion ordeletion occurs, the specification is deemed to contain the group asmodified thus fulfilling the written description of all Markush groupsused in the appended claims.

Unless otherwise indicated, all numbers expressing a characteristic,item, quantity, parameter, property, term, and so forth used in thepresent specification and claims are to be understood as being modifiedin all instances by the term “about.” As used herein, the term “about”means that the characteristic, item, quantity, parameter, property, orterm so qualified encompasses a range of plus or minus ten percent aboveand below the value of the stated characteristic, item, quantity,parameter, property, or term. Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the specification andattached claims are approximations that may vary. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical indication shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques. Notwithstandingthat the numerical ranges and values setting forth the broad scope ofthe invention are approximations, the numerical ranges and values setforth in the specific examples are reported as precisely as possible.Any numerical range or value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Recitation of numerical ranges ofvalues herein is merely intended to serve as a shorthand method ofreferring individually to each separate numerical value falling withinthe range. Unless otherwise indicated herein, each individual value of anumerical range is incorporated into the present specification as if itwere individually recited herein.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the present invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein is intended merely to betterilluminate the present invention and does not pose a limitation on thescope of the invention otherwise claimed. No language in the presentspecification should be construed as indicating any non-claimed elementessential to the practice of the invention.

Specific embodiments disclosed herein may be further limited in theclaims using consisting of or consisting essentially of language. Whenused in the claims, whether as filed or added per amendment, thetransition term “consisting of” excludes any element, step, oringredient not specified in the claims. The transition term “consistingessentially of” limits the scope of a claim to the specified materialsor steps and those that do not materially affect the basic and novelcharacteristic(s). Embodiments of the present invention so claimed areinherently or expressly described and enabled herein.

All patents, patent publications, and other publications referenced andidentified in the present specification are individually and expresslyincorporated herein by reference in their entirety for the purpose ofdescribing and disclosing, for example, the compositions andmethodologies described in such publications that might be used inconnection with the present invention. These publications are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing in this regard should be construed as an admissionthat the inventors are not entitled to antedate such disclosure byvirtue of prior invention or for any other reason. All statements as tothe date or representation as to the contents of these documents isbased on the information available to the applicants and does notconstitute any admission as to the correctness of the dates or contentsof these documents.

1. A method of treating a demyelination-related disorder, the methodcomprising the step of administering to an individual in need thereof atherapeutically effective amount of a RXR agonist with bothremyelination promotion and immunomodulatory activities, whereinadministration of the RXR agonist treats the demyelination-relateddisorder in the individual by both promoting remyelination of neuronsand modulating the individual's immune system.
 2. The method accordingto claim 1, wherein the immunomodulatory activity comprises increasingthe number of Treg cells in the individual.
 3. The method according toclaim 1, wherein the immunomodulatory activity comprises decreasing thenumber of Th17 cells in the individual.
 4. The method according to claim1, wherein the immunomodulatory activity comprises increasing the numberof Treg cells and decreasing the number of Th17 cells in the individual.5. The method according to claim 1, wherein the RXR agonist is acompound having the structure of formula I:

Wherein Z is a radical shown in Formula II:

Y is cycloalkyl or cycloalkenyl of 3 to 8 carbons optionally substitutedwith one or two R⁴ groups, or Y is selected from phenyl, pyridyl,thienyl, furyl, pyrrolyl, pyridazinyl, pyrimidiyl, pyrazinyl, thiazolyl,oxazolyl, and imidazolyl, the groups being optionally substituted withone or two R⁴ groups, the divalent Y radical being substituted by the Zand —(CR¹═CR¹═CR¹═CR¹)— groups on adjacent carbons; R¹ and R²independently are H, lower alkyl or fluoroalkyl; R³ is hydrogen, loweralkyl, Cl or Br; R⁴ is lower alkyl, fluoroalkyl or halogen, and B ishydrogen, —COOH or a pharmaceutically acceptable salt thereof, —COOR⁸,—CONR⁹R¹⁰, —CH₂OH, —CH₂OR¹¹, —CH₂OCOR¹¹, —CHO, —CH(OR¹²)², —CHOR¹³O,—OCOR⁷, —CR⁷(OR¹²)₂, —CR⁷OR¹³O, or tri-lower alkylsilyl, where R⁷ is analkyl, cycloalkyl or alkenyl group, containing 1 to 5 carbons, R⁸ is analkyl group of 1 to 10 carbons, a cycloalkyl group of 5 to 10 carbons ortrimethylsilylalkyl where the alkyl group has 1 to 10 carbons, or R⁸ isphenyl or lower alkylphenyl, R⁹ and R¹⁰ independently are hydrogen, analkyl group of 1 to 10 carbons, or a cycloalkyl group of 5-10 carbons,or phenyl or lower alkylphenyl, R¹¹ is lower alkyl, phenyl or loweralkylphenyl, R¹² is lower alkyl, and R¹³ is divalent alkyl radical of2-5 carbons; and n is 1 or
 2. 6. The method according to claim 1,wherein the RXR agonist is a compound having the structure of formulaXII:

wherein R is H, lower alkyl or 1 to 6 carbons, or a pharmaceuticallyacceptable salt of the compound.
 7. The method according to claim 1,wherein the RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid, and has the structure of formula XXIX:


8. The method according to claim 1, wherein the demyelination-relateddisorder is a central nervous system disorder.
 9. The method accordingto claim 1, wherein the central nervous system disorder is multiplesclerosis, diffuse white matter injury in pre-term infants,neuromyelitis optica, acute disseminated encephalomyelitis, Marburgmultiple sclerosis, diffuse myelinoclastic sclerosis (Schilder'sdisease), Balo concentric sclerosis, solitary sclerosis, optic neuritis,transverse myelitis, amyotrophic lateral sclerosis, leukodystrophy(multiple variants, e.g. adrenoleukodystrophy, adrenomyeloneuropathy),Parkinson's disease, Alzheimer's disease, progressive supranuclearpalsy, stroke, traumatic brain injury, radiation inducedneuroinflammation, radiation somnolence syndrome, Devic's disease,inflammatory demyelinating diseases, a CNS neuropathies like thoseproduced by vitamin B12 deficiency, central pontine myelinolysis,myelopathies like Tabes dorsalis (syphilitic myelopathy),leukoencephalopathies like progressive multifocal leukoencephalopathy,or leukodystrophies.
 10. The method according to claim 1, wherein thedemyelination-related disorder is multiple sclerosis.
 11. The methodaccording to claim 1, wherein the demyelination-related disorder isradiation-induced central nervous system inflammation.
 12. The methodaccording to claim 1, wherein the demyelination-related disorder is aperipheral nervous system disorder.
 13. The method according to anyclaim 1, wherein the peripheral nervous system disorder isGuillain-Barré Syndrome, acute inflammatory demyelinatingpolyneuropathy, chronic inflammatory demyelinating polyneuropathy,demyelinating diabetic neuropathy, progressive inflammatory neuropathy,drug- or toxin-induced neuropathy, such as chemotherapy-inducedneuropathy or organophosphate-induced neuropathy, anti-MAG peripheralneuropathy, Charcot-Marie-Tooth Disease, or copper deficiency.
 14. Themethod according to claim 1, wherein the therapeutically effectiveamount is about 0.001 mg/kg/day to about 100 mg/kg/day.
 15. The methodaccording to claim 14, wherein the therapeutically effective amount isabout 0.1 mg/kg/day to about 10 mg/kg/day.
 16. The method according toclaim 1, wherein the therapeutically effective amount is about 0.01mg/m²/day to about 100 mg/m²/day.
 17. The method according to claim 16,wherein the therapeutically effective amount is about 15 mg/m²/day toabout 60 mg/m²/day.
 18. The method according to claim 1, wherein the RXRagonist is administered by nasal administration.
 19. The methodaccording to claim 1, wherein treatment with the RXR agonist reduces atleast one symptom of the demyelination-related disorder, wherein the atleast one symptom reduced is inflammation, fatigue, dizziness, malaise,elevated fever and high body temperature, extreme sensitivity to cold inthe hands and feet, weakness and stiffness in muscles and joints, weightchanges, digestive or gastrointestinal problems, low or high bloodpressure, irritability, anxiety, or depression, blurred or doublevision, ataxia, clonus, dysarthria, fatigue, clumsiness, hand paralysis,hemiparesis, genital anesthesia, incoordination, paresthesias, ocularparalysis, impaired muscle coordination, weakness (muscle), loss ofsensation, impaired vision, neurological symptoms, unsteady gait,spastic paraparesis, incontinence, hearing problems, or speech problems.20. A method of treating multiple sclerosis, the method comprising thestep of administering to an individual in need thereof a therapeuticallyeffective amount of a RXR agonist, wherein the RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid; and wherein administration of the RXR agonist treatsthe multiple sclerosis in the individual.
 21. A method of treating a CNSdemyelination-related disorder, the method comprising the step ofadministering to an individual in need thereof a therapeuticallyeffective amount of a RXR agonist, wherein the RXR agonist is3,7-dimethyl-6(S),7(S)-methano,7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]2(E),4(E)heptadienoic acid; and wherein administration of the RXR agonist treatsthe CNS demyelination-related disorder in the individual and wherein theRXR agonist is delivered directly to the CNS of the individual byintrathecal administration, epidural administration, cranial injectionor implant, or nasal administration.